Substance interaction with the lung resident cell membrane components

1333-86-4

Carbon black

ACETYLENE BLACK Acetylene Black AD 100 Acetylene Black HS 100 Acetylene CB AcryJet Black 357 Acticarbon AC 35 Ajack Black 5021 AM Black AM Black 9700 Americhem 11793F1 Black Animal bone charcoal Aqua Black HA 3 Aqua-Black 001 Aqua-Black 162 Aquablak Aquablak 15 Aquablak 235A Aquablak 245 Aquablak 320 Aquadisperse Black CB-EP Aqualour Black Aquis II KW 3729 Arosperse 15 Arosperse 15-213 Arosperse 15-239 Asahi 70HAF Asahi 75N339 Asahi Black 3078 Asahi Black HS 500 Asahi Thermal Black FT Asahi Thermal FT Asahi Thermal MT Asahithermal Aurasperse W 7017 Austin Black BASIS PIGMENT BLACK 7 Baydur Blackpaste DN Bayscript VPSP 20016 Black BLN Black DCF 50 Black FW Black No. 2 Black Pearls Black Pearls 1000 Black Pearls 1100 Black Pearls 120 Black Pearls 130 Black Pearls 1300 Black Pearls 1300A73 Black Pearls 160 Black Pearls 2000 Black Pearls 280 Black Pearls 3200 Black Pearls 3500 Black Pearls 3550 Black Pearls 3700 Black Pearls 420 Black Pearls 430 Black Pearls 4350 Black Pearls 4560 Black Pearls 460 Black Pearls 4750 Black Pearls 480 Black Pearls 490 Black Pearls 6100 Black Pearls 700 Black Pearls 800 Black Pearls 8500 Black Pearls 880 Black Pearls 900 Black Pearls L Black Y 200 BLACK, CARBON BLACK PIGMENT Blackhole Bonjet Black 850L Bonjet Black CW 1 Bonjet Black CW 2 C.I. 77268:1 C.I. Food Black 3 C.I. Pigment Black 6 C.I. Pigment Black 7 C.I. PIGMENT BLACK 7, CARBON BLACK C/B-G-SVH Cabot Black Pearls 4350 Cabot N 326 Calblack N 220 Calgon RBDA Carbocolor Carbodis 100 Carbodis 80 Carbon blaack Carbon Black 100 Carbon Black 2000 Carbon Black 2300 Carbon Black 25 Carbon Black 25B Carbon black 2600 Carbon Black 2650 Carbon Black 30 Carbon Black 32 Carbon Black 40 Carbon Black 4350 Carbon black 44 Carbon Black 45 Carbon Black 45L Carbon Black 50 Carbon Black 52 Carbon Black 850 Carbon Black 960 Carbon Black 980 CARBON BLACK PIGMENT Carbon black Sp Carbon ECD Carbon ECP 600JD Carbon ISAF Carbon MA 7 CD 2005HT1000 CD 2005HT1500 CD 2005HT2000 CD 7055 Ultra Celgreen HBMD-D CF Black PC CFP-FF 949K Channel black Channel Black 100 Char, from refuse burner Chesacarb Chesacarb E Chesacarb EC Chesacarb ECA Chesacarb K 2 Chezacarb A Chezasorb COAL SOOT Codispersion 30R20 Colanyl Black N Collophite Color Black FW 1 Color Black FW 18 Color Black FW 18G Color Black FW 2 Color Black FW 200 Color Black FW 220 Color Black FW 285 Color Black S 160 Color Black S 170 Colormatch DR 20845 Colormatch DR 20942 Colormatch UVS 20519 Columbian Raven 350 Conductex 40-200 Conductex 40-220 Conductex 900 Conductex 950 Conductex 975 Conductex 975 Ultra Conductex 975U Conductex CC 40-220 Conductex N 472 Conductex SC Conductex SC Ultra Conductex SC-U Condutex XC 72 Continex N 330 Continex N 356 Corasol C 30 Corax A Corax L Corax MAF Corax N 100 Corax N 110 Corax N 115 Corax N 121 Corax N 220 Corax N 234 Corax N 234G Corax N 326 Corax N 330 Corax N 339 Corax N 358 Corax N 375 Corax N 539 Corax N 550 Corax N 600 Corax N 762 Corax N 772 Corax N 990 Corax P Corpren CB 3000 Covarine W 9793 D and C Black No. 2 D&C Black No. 2 DC Black 7100 Degussa AG-FW 2V Degussa Black FW Degussa FW 200 Denka Acetylene Black Denka Acetylene Black CBA Denka Black AB 12 Denka Black AB 6 Denka Black AB 7 Denka Black DH Denka Black FX 35 Denka Black HS 100 Denka Black HS 200 Denka Black NC 75 Denka Black OAB 100 Denka Black ST 100 Denka HS 100 Denkablack Dequssa FW 2V Dermmapol Black G Derussol P 130 Diablack Diablack 2350 Diablack 2400B Diablack 30 Diablack 3030 Diablack 3030B Diablack 3050B Diablack 3150B Diablack 3230B Diablack 3250 Diablack 33 Diablack 3500B Diablack 3950 Diablack 45L Diablack 52 Diablack 960B Diablack A Diablack E Diablack G Diablack H Diablack HA Diablack HS-SAF Diablack I Diablack L Diablack LH Diablack LI Diablack LM-SFR Diablack LR Diablack MA 100 Diablack MA 14 Diablack MA 220 Diablack MA 230 Diablack MA 40 Diablack MA 650 Diablack MA 70 Diablack MA 77 Diablack MA 8 Diablack MA 800 Diablack MA 8B Diablack N 220 Diablack N 234 Diablack N 234M Diablack N 339 Diablack N 550 Diablack N 550M Diablack SA Diablack SF Diablack SH Diablack UX 10 Disperse Black SD 9020 Disperse HG 935 Durex O Dymic MBR 717 Ecorax 1670 Ecorax 1720 ECX-A 304NW EG Black G 30 Eldic EC 8013 Elftex Oil Pellets Elftex P 100 Elftex TB Elftex TP EM Black K 16 EM Color Black K 16 Emacol Black C Emacol NS Black 4901 Ensaco 150G Ensaco 210G Ensaco 23MM Ensaco 250G Ensaco 260G Ensaco 350G EP 510 Black EP 564 Black Euderm Black D-B Farbruss 200 Farbruss FW 1 Farbruss FW 18 Farbruss S 160 Flame Black Flammruss 101 Flexiverse Black 7 Flexobrite Black 43/77VB FP Black 308 Fuji AS Black Fuji AS Black 810 Fuji SP Black 8306 Fuji SP Black 8922 Fuji VL Black Furex N 772 Furnace black Furnace Black 101 Furnace black 2300 Furnace Black 3050 Furnace Black 3600B Furnace Black 750B Furnex N 765 GA Black 12031 Gas black GP Black 4613 Grand Black YT 100 Graphon C Graphtol Black BLN GRAY, CARBON BLACK PIGMENT Hi-Black 150B Hi-Black 160B Hi-Black 40B2 Hi-Black 41 Hi-Black 420B Hi-Black HI Highblack 40B1 Himicron K Black 0542 Holcobatch C Black 93909 Hostajet BLK-VP 2676 Huber N 990 Inorganic,carbon black Irgafin Black CN ISAF-LS Ketjen 600JD Ketjen Black A 8 Ketjen Black EC-P 600 Ketjen Black W 310A Ketjen EC-DJ 600 Ketjenblack Ketjenblack 300 Ketjenblack 300J Ketjenblack 600JD Ketjenblack BC Ketjenblack EC 300 Ketjenblack EC 300N Ketjenblack EC 310 Ketjenblack EC 310NW Ketjenblack EC 3750 Ketjenblack EC 600 Ketjenblack EC 600DJ Ketjenblack EC 600J Ketjenblack EC 8002 Ketjenblack EC-DJ 500 Ketjenblack EC-DJ 600 Ketjenblack EC-P Ketjenblack EC-P 600JD Ketjenblack EC-X Ketjenblack EP-C 600JD Ketjenblack EP-DJ 600 Ketjenblack ES Ketjenblack FC Ketjenblack KC Ketjenblack W 310A KOG-CLS L 1/8 Black MA 100 Lamp Black Lamp Black 101 Lamp Black 888-9907B Lamp Black LB 101 Pigment I Lampblack Levanyl Black A-SF Levanyl Black B-LF Levanyl Black BZ Levanyl Black N-LF Levanyl B-LF Levanyl N-LF Liojet WD Black 002C Lion Paste W 310A Lion Paste W 311N Lion Paste W 376R Luconyl Black 0060 Luconyl Black 0066 Magecol 888 MC Black 082E Metanex D Methane black MHI Black 209 MHI Black 217 MHI Black 220 MHI Black 4962M MHI Black 8704M MHI Black 971 Microdis I Microjet Black CW 1 Microjet Black M 800 Microjet C Microlith Black CA Microlith Black C-K Microlith Black C-T Microlith Black C-T 85095 Microlith Black C-WA Microlith Black M Micropigmo Black WM-BK 5 Micropigmo WM-BK 5 Microsol Black 2B Mikuni 0542 Mitsubishi 1000 Mitsubishi 20B Mitsubishi 2400 Mitsubishi 2400B Mitsubishi 258 Mitsubishi 260 Mitsubishi 2770B Mitsubishi 30 Mitsubishi 3030 Mitsubishi 3050 Mitsubishi 30B Mitsubishi 3150 Mitsubishi 3400 Mitsubishi 40 Mitsubishi 44 Mitsubishi 45 Mitsubishi 47 Mitsubishi 50 Mitsubishi 650 Mitsubishi 900 Mitsubishi Carbon 10 Mitsubishi Carbon 25 Mitsubishi Carbon 40 Mitsubishi Carbon 44 Mitsubishi Carbon 45 Mitsubishi Carbon 50 Mitsubishi Carbon 52 Mitsubishi Carbon Black 2000 Mitsubishi Carbon Black 2600 Mitsubishi Carbon Black 3050 Mitsubishi Carbon Black 33 Mitsubishi Carbon Black 44 Mitsubishi Carbon Black 900 Mitsubishi Carbon Black 950 Mitsubishi Carbon Black 990 Mogul A Mogul E Mogul L Molacco Monaprin Black XBE Monarch 1000 Monarch 1100 Monarch 120 Monarch 1300 Monarch 1400 Monarch 1500 Monarch 280 Monarch 460 Monarch 4750 Monarch 580 Monarch 700 Monarch 800 Monarch 880 Monarch 900 Monarch Black 1300 Monarch Fluffy 435 Monarch M 800 Monocol 35T Monocol 37T Monocol MX 230 MPC Black MPS 1100 Black MPS 1504 Black MT Carbon Mulco 8162 Black Multilac A 903 Black N 121HT1000 N 121HT1500 Nanom Black FB-S negro de carbon Neocon 600P Neo-Spectra Beads AG Neo-Spectra Mark I Neo-Spectra Mark II Neotex 100H New Lacqutimine Black FLPR Nicabeads PC 0520 Nicabeads PC 1020 Nichilon 105 Nigros F Nigros G Nigros I Nigros K Nipex 160IQ NIPex 170IQ Nipex 1801Q Nipex 180IQ Niteron 10K Niteron 200 Niteron 2000 Niteron 200B Niteron 200H Niteron 200IS Niteron 200LG Niteron 200MP Niteron 300 Niteron 300B Niteron 300MP Niteron 3350 Niteron 410 Niteron 55A Niteron 55G Niteron FEF 10 Noir de carbone Nylofil Black BLN Oil Furnace Black 44B OneSource 9292B3546 Tint Orient Black N 330 OTS-S/A OTS-S/B Panther 17FB PCM-DH 1012 Peach black Pearl Black 2000 Peerless MK II Pelletex Pelletex SRF PEM 8080BKMB Peony Black 30940 Peony Black F 30940 Peony Black FF 30940MM Permablack 2847A Permablack 900 Permablak 663 PEX 998004 Black PEX 998023 Black Philblack Philblack N 220 Philblack N 550 Philblack N 765 Philblack O Picachem B 9 Pigmatex Black T Pigment Black 07 Pigment Black 6 Pigment Black 7 Pigment Black FW 200 Beads Plasblak 3037 Plasblak EV 1755 Plasblak PE 1371 Plasblak PE 1851 Plasblak PE 2614 Plasblak PE 2640 Plasblak PE 2642 Plasblak PE 2648 Plasblak PE 2662 Plastblak EV 1755 PLWTEXG Pollux Black PM-B Pollux Black PP 8TO85 Pollux Black PP-B Porousblack Printex Printex 140 Printex 140T Printex 140U Printex 140V Printex 150T Printex 200 Printex 300 Printex 400 Printex 75R Printex A Printex Alpha Printex EC 2 Printex F 80 Printex Falpha Printex G Printex L Printex L 1 Printex L 40 Printex L 6 Printex L-SQ Printex P Printex U Printex V Printex XA Printex XE Printex XE 2 Printex XE 2B Printex XE-II Printex XPB 080 Product 11793F1 Black PSM Black Pureblack SCD 205 Pureblack SCD 530 Pureblack SCD 545 Pureblack SCD 550 Pureblack SCD 555 Purex HS 25 Purex HS 45 Pyroblack 3S Pyroblack 5AF Pyroblack 5F Pyroblack 7007 Pyroblack 7F Raven 1000BDS Raven 1060B Raven 1100 Ultra Raven 1190 Ultra Raven 12200 Raven 1255B Raven 2500 Ultra Raven 3600 Ultra Raven 420 Dense Raven 430 Ultra Raven 5000 Ultra II Raven 5000UIII Raven 760 Ultra Raven 780 Ultra Raven 860 Ultra Raven 880 Ultra Raven Beads Raven Black Raven C Raven P-FE/B Rebonex H Rebonex HS Rebonex I Rebus Carbon Black 1106 Regal 1250R Regal Black 250R Regal L Regal R 330 Regal SRF Regal SRF-S Renol Black R-HW Renol Black RT-HW Royal Spectra Ryudye W Black RC S 2400 Black 4 SA Black DY 6 Sandye Black P Sandye Black P Paste 2904 Sandye Black P Paste SL Sandye DP Black P 2904 Sandye Super Black C Sanylene Black EMA Sashinekka E Seast 116HM Seast 116MAF Seast 300HAF-LS Seast F Seast FM Seast FY Seast G 116 Seast GS Seast G-SO Seast G-SVH Seast ISAF Seast KH Seast M Seast N Seast N 211 Seast N 300 Seast NB Seast NH Seast S Seast SO Seast SOP Seast SP Seast SP-SRF-LS Seast S-SRF Seast SY-SRF-HS 8500 Seast V Seika Seven Servacarb Sevacarb MT Sevacarb MT-CI Sevacarb MT-CL Sevacarb MT-LS Sevacarb SC-N 990 Sevalco Shawinigan ABC 55-22913 Shawinigan Black Shawinigan Black AB 100 Shawinigan Black C 55 Shoblack Shoblack FEF Shoblack IP 200 Shoblack IP 600 Shoblack MAF Shoblack N 110 Shoblack N 200 Shoblack N 220 Shoblack N 2201 Shoblack N 234 Shoblack N 326 Shoblack N 326M Shoblack N 330 Shoblack N 330T Shoblack N 335 Shoblack N 339 Shoblack N 351 Shoblack N 550 Shoblack N 660 Shoblack N 762 Shoblack S 118 Sicoflush L Black 0054 Sicoflush L Black 0063 Sicoflush P Black 0054 Sohn Black Soot FR 101 SOOTS SP Black 8922 SP Black AS 1192 SP Black AS 1193 Special black 100 Special black 15 Special Black 250 Special Black 250P Special Black 350 Special black 4 Special Black 4A Special black 5 Special black 6 Special Black Bayer A-SF Special Black S 160 Spheron 4000A Spheron 5000 Spheron 5000A SRF Black SRF Carbon SS Fujikura Black Statex 550CBL Statex B Statex B 12 Statex G Statex GH Statex M 70 Statex MRG Statex MT Statex MT 90 Statex N 200 Statex N 550 Statex N 650 Sterling 1120 Sterling 142 Sterling 2320 Sterling 4620 Sterling 6630 Sterling 6630A Sterling FT Sterling FT-FF Sterling MT Sterling MTG Sterling N 550 Sterling N 765 Sterling NS Sterling NS 1 Sterling R Sterling R-V 7688 Sterling RX 76 Sterling SO Sterling SO 1 Sterling SO-N 550 Sterling SR Sterling V Sterling VH Sterling VL Sun Black LHD 9303 Sunblack 605 Sunblack X 15 Sunblack X 25 Sunblack X 45 Sunsperse Black LHD 9303 Supandai PLR-FC 121 Super Colloid 6 Supercarbovar Suprapal Black 2XS8A734 Suprapal Black X 60 T 1375 Black (R) EC TB 575 Black S-T 2 Termax N 990 Termoks 277KhIT Thermal Black Thermal MT-CB Thermax Thermax 907 Thermax Floform CC-N 990 Thermax Floform N 990 Thermax Medium Thermal Black MT Thermax MT Thermax N 990 Thermax N 991 Thermax Stainless Thermax Ultra Pure N 991 Tintacarb 300 Tintacarb 435 Toka Black 3800 Toka Black 3855 Toka Black 3885 Toka Black 4400 Toka Black 4400F Toka Black 4500 Toka Black 4500F Toka Black 4550F Toka Black 5500 Toka Black 7100 Toka Black 7100F Toka Black 7240 Toka Black 7350 Toka Black 7350F Toka Black 7360SB Toka Black 7550 Toka Black 7550F Toka Black 7700 Toka Black 8300 Toka Black 8500 Toka Black 8500F Tokai Carbon 600A Tokai Carbon ESR Toner Black 020 TVP 0623 BLACK UK-Vulcan P Ultrabond Black K UNA 4 Unisperse Black B-PI Unisperse Black C-E 2N United 3017 United SL 90 ValKan 72XC VC Black Vulcan 1380 Vulcan 1391 Vulcan 9A32 Vulcan C Vulcan J Vulcan K Vulcan M Vulcan P Vulcan PF 300 Vulcan VX 72 Vulcan X 72 Vulcan XC Vulcan XC 200 Vulcan XC 272 Vulcan XC 305 Vulcan XC 72 Vulcan XC 72R Vulcan XC 72R-GP3820 WA Black A 250 Witcoblack 100 Xfast Black 0066 XPB-AT 1234

DTXSID7051216

NOCAS

Diesel engine exhaust

Diesel Exhaust DE

DTXSID1024043

PR:000001096

PR Toll-like receptor

PR:000001155

PR Toll-like receptor 4

FMA:84050

FMA Cytokine

FMA:241981

FMA Chemokine

FMA:86578

FMA Interleukin

CL:0009002

CL inflammatory cell

CL:0000235

CL macrophage

CL:0000066

CL epithelial cell

CHEBI:26523

CHEBI reactive oxygen species

GO:0090734

GO site of DNA damage

GO:0005694

GO chromosome

GO:1990391

GO DNA repair complex

CL:0000077

CL mesothelial cell

UBERON:0002048

UBERON lung

GO:0002221

GO pattern recognition receptor signaling pathway

GO:0002224

GO toll-like receptor signaling pathway

GO:0034142

GO toll-like receptor 4 signaling pathway

GO:0002534

GO cytokine production involved in inflammatory response

GO:0090195

GO chemokine secretion

GO:0006956

GO complement activation

GO:0006954

GO inflammatory response

GO:0042116

GO macrophage activation

GO:0008219

GO cell death

GO:1903409

GO reactive oxygen species biosynthetic process

GO:0042769

GO DNA damage response, detection of DNA damage

D009154

MESH mutation

GO:0031052

GO chromosome breakage

MP:0008866

MP chromosomal instability

MP:0008058

MP abnormal DNA repair

GO:0008283

GO cell proliferation

HP:0100526

HP Neoplasm of the lung

MP:0008014

MP increased lung tumor incidence

WIKI increased

nanoparticles

2016-12-21T09:40:06

welding fumes

2022-05-25T07:02:57

Carbon black

2022-05-25T07:03:26

Diesel engine exhaust

2021-08-06T08:41:15

2021-09-28T08:55:47

nanomaterials

2021-04-22T09:28:39

Titanium dioxide nanoparticles

2022-08-29T08:22:45

Propylene oxide

2016-11-29T18:42:27

Reactive oxygen species

2017-06-16T08:32:10

2017-08-15T10:43:27

Ionizing Radiation Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.

Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).

2019-05-03T12:36:36

2019-05-07T12:12:13

High aspect ratio material

2019-08-13T04:38:40

10090

NCBI mouse

10116

NCBI rat

WCS_9606

common toxicological species human

10116

NCBI rats

WikiUser_28

Vertebrates

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

WCS_35525

common ecological species crustaceans

WCS_4472

common ecological species Lemna minor

WCS_7955

common ecological species zebrafish

WikiUser_17

mammals

Substance interaction with the lung resident cell membrane components

Interaction with the lung cell membrane

Molecular

The human lung consists of approximately 40 different resident cell types that play different roles during homeostasis, injury, repair and disease states (Franks et al., 2008; Luettich et al., 2021). Of these, resident airway epithelial cells, alveolar/interstitial macrophages and dendritic cells are well characterised for their ability to sense the danger upon interaction with harmful substances and relay the message to mount the necessary immune/inflammatory response. The resident macrophages are present in all tissues, and in a steady state, macrophages contribute to epithelial integrity, survey the tissue for invading pathogens or chemicals and maintain an immunosuppressive environment. Their main function is to clear the incoming irritants and microbes. They are named differently based on the tissue type and their specific functions (Kierdorf et al., 2015). Substance interactions: The chemicals or pathogens interact with cellular membrane to gain access to the organisms’ interior. A predominant interaction mechanism involves the recognition of innate immune response agonists by pattern recognition receptors (PRRs) present on resident cells such as epithelial and alveolar macrophages. PRRs are also present on other immune and parenchymal cells. PRRs can be activated by two classes of ligands. Pathogen associated molecular patterns (PAMPs) are microbial molecules derived from invading pathogens. PAMPs will not be discussed further as pathogens are not the focus for the AOP presented here. The other class of ligands are called danger associated molecular patterns (DAMPs) that include cellular fragments, nucleic acids, small molecules, proteins and even cytokines released from injured or dying cells (Bianchi, 2007). Most fibrogenic stressors discussed in this AOP act via DAMPs-driven PRR activation. High aspect ratio (HAR) materials such as asbestos or carbon nanotubes (CNTs) pierce the cellular membrane of epithelial cells or resident macrophages resulting in cell injury or non-programmed cellular death. Alveolar macrophages trying to engulf HAR fibres that are long and stiff undergo frustrated phagocytosis because of their inability to engulf the piercing fibres and subsequently lead to cell injury (Boyles et al., 2015; Brown et al., 2007; Donaldson K et al., 2010; Dörger et al., 2001; Mossman and Churg, 1998). The cellular debris from injured or dying cell then serves as ligands for PRRs (Nakayama, 2018), leading to cell activation. In case of pro-fibrotic insoluble particles such as silica, coal dust and nanomaterials (NMs), the particle adsorbed opsonins such as immunoglobulins, complement proteins, or serum proteins act as ligands to the receptors on the macrophage cell surface (Behzadi et al., 2017). The tissue response to these materials resembles that observed following foreign body invasion in lungs. Toll-like receptors (TLRs) are highly conserved PRRs that are associated with fibrogenic stressors (Desai et al., 2018). Inhibition of TLR-4 is protective against bleomycin-induced fibrosis (Li et al., 2015). However, the exact role and mechanisms by which TLRs mediate lung fibrosis are yet to be uncovered and some studies have shown TLRs to be protective against lung fibrosis (Desai et al., 2018). Asbestos and silica crystals are suggested to engage scavenger receptors present on the macrophages. Mice deficient in class A scavenger macrophage receptor with collagenous structure (MARCO) are shown to induce reduced fibrogenic response following chrysotile asbestos exposure; although, the direct binding of MARCO by asbestos is not investigated in the study (Murthy et al., 2015). In case of soluble substances such as bleomycin, paraquat (Dinis-Oliveira et al., 2008) (N,N'-dimethyl-4, 4′-bipyridinium dichloride) and other soluble fibrogenic chemicals, direct damage of lung epithelial cells and resulting cellular debris or secreted cytokines (DAMPs) serve as triggers for downstream cascading pro-inflammatory events, tissue injury and fibrosis. Engagement of PRRs and consequent cell activation is observed in various organisms including flies and mammals (Denholm and Phan, 1990; Matzinger, 2002).

Detection of DAMPs or homeostasis-altering molecular processes: Cellular interaction with substances or particles can be measured by assessing the release of DAMPs from stressed, injured or dying cells - indicative of binding of PRRs on the cell surface. Release of DAMPs is reflective of substance interaction with resident cells and their activation, a key step in the process of inflammation. The release of DAMPs can be measured by the techniques listed in the published literature (Nikota et al., 2017; Rabolli et al., 2014; Suwara et al., 2014). Targeted enzyme-linked immunosorbent assays (ELISA) (routinely used and recommended): ELISA  – permits quantitative measurement of antigens in biological samples. For example, in a cytokine ELISA (sandwich ELISA), an antibody (capture antibody) specific to a cytokine is immobilised on microtitre wells (96-well, 386-well, etc.). Experimental samples or samples containing a known amount of the specific recombinant cytokine are then reacted with the immobilised antibody. Following removal of unbound antibody by thorough washing, plates are reacted with the secondary antibody (detection antibody) that is conjugated to an enzyme such as horseradish peroxidase, which when bound, will form a sandwich with the capture antibody and the cytokine (Amsen and De Visser, 2009). The secondary antibody can be conjugated to biotin, which is then detected by addition of streptavidin linked to horseradish peroxidase. A chromogenic substrate can also be added, which is the most commonly used method. Chromogenic substrate is chemically converted by the enzyme coupled to the detection antibody, resulting in colour change. The amount of colour detected is directly proportional to the amount of cytokine in the sample that is bound to the capture antibody. The results are read using a spectrophotometer and compared to the levels of cytokine in control samples where cytokine is not expected to be secreted or to the samples containing known recombinant cytokine levels. Interleukin (IL)-1α and -1β is activated or secreted into the cytosol following stimulus (Di Paolo and Shayakhmetov, 2016). Targeted ELISA can be used to quantify IL-1α  or IL-1β that is released in the culture supernatant of the cells exposed to toxicants, in bronchoalveolar lavage fluid and serum of exposed animals. The assay is also applicable to human serum, cerebrospinal fluid, and peritoneal fluids. Similarly, other alarmins can also be quantified by ELISA. Western blot is another method that can be used to quantify the release of various alarmins using specific antibodies. ELISA or real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays can also be used to quantify the expression of genes or proteins that are regulated by the receptor binding – e.g. downstream of TLR binding. Frustrated phagocytosis and cellular uptake of NMs: In vitro, interaction of NMs with the cellular membrane is investigated by assessing their uptake by lysosomes (Chen et al., 2013; Nel et al., 2009; Varela et al., 2012). Immunohistochemistry methods targeting lysosome specific proteins are regularly employed for this purpose. In co-localisation experiments, lysosomal marker Lysosomal-associated membrane protein 1 (LAMP1) antibody is used to detect particle co-localisation with lysosomes. A combination of Cytoviva hyperspectral microscope and immunolocalisation (Decan et al., 2016) or confocal microscopy to visualise co-localisation of fluorescence labelled nanoparticles with lysosomal markers have been used. Frustrated phagocytosis is assessed using microscopic techniques such as time-lapse microscopy, backscatter electron microscopy and others (Donaldson et al., 2010; Murphy et al., 2012; Padmore et al., 2017; Pascolo et al., 2013; Schinwald et al., 2012). In addition, MIE 1668 of AOP303 notes other indirect methods for measuring frustrated phagocytosis.   Cellular co-culture models of the pulmonary epithelium: Complex co-culture systems, such as those containing epithelial cells and immune cells, better model the environment of the lung epithelium and can be used to study the interaction of potentially pro-fibrotic fibres and particles with resident lung cells. This type of model has been used, alongside electron microscopy, to study lung cell interactions with CNTs following 24 h in vitro exposure (Clift et al., 2014). More recently, the EpiAlveolar model, which contains primary human alveolar epithelial cells, endothelial cells, as well as fibroblasts was assessed for its ability to predict fibrosis induced by CNTs (Barasova et al., 2020). Using laser scanning, fluorescence, and enhanced darkfield microscopy, CNT interaction with the resident cells of the model was shown, and this interaction induced the formation of holes in the epithelial model (Barasova et al., 2020). While new co-culture models are a better recapitulation of the native lung environment as compared to traditional mono-cultures, the increased complexity necessitates enhanced expertise in tissue culture techniques, and can make them less practical as compared to submerged mono culture methods.  Ex vivo model of the lung – Precision cut lung slices (PCLS): Even closer to the in vivo condition than co-culture models, PCLS techniques capture the native lung architecture, cell-cell communication and cellularity of the lung. Advancement in culturing and cryopreservation techniques has increased accessibility and use of PCLS for longer term studies (Bai et al., 2016, Neuhaus et al., 2017). These slices can be cultured ex vivo for up to a week with minimal reduction in viability, and the technique has recently been assessed for its applicability to assess nanomaterial induced fibrosis ex vivo (Rahman et al., 2020). Using multi-walled carbon nanotubes (MWCNTs) and darkfield microscopy, interaction between the nanofibers and the lung epithelium could be determined. The main downside of this technique is the animal requirement, which precludes their use in a first-pass screening context for the MIE.

Human, mouse, rat. Although the expression of DAMPs following exposure to pro-fibrotic substances is not assessed across species, it is known that alarmins are released after trauma or injury, and their release is important for initiating the inflammatory response in all species including humans. The immediate acute inflammatory response involving DAMP signalling is also observed in human idiopathic pulmonary fibrosis (IPF); however, anti-inflammatory drugs have proven ineffective for treating IPF. Danger signalling axis including uric acid, adenosine triphosphate and IL-33/ST2 has been proven to promote lung fibrosis in animals.

CL:0000255

CL eukaryotic cell

High Male

High

Adults

High High High

1. Amsen D, de Visser KE, Town T. Approaches to determine expression of inflammatory cytokines. Methods Mol Biol. 2009;511:107-42. doi: 10.1007/978-1-59745-447-6_5. 2. Bai Y, Krishnamoorthy N, Patel KR, Rosas I, Sanderson MJ, Ai X. Cryopreserved Human Precision-Cut Lung Slices as a Bioassay for Live Tissue Banking. A Viability Study of Bronchodilation with Bitter-Taste Receptor Agonists. Am J Respir Cell Mol Biol. 2016 May;54(5):656-63. doi: 10.1165/rcmb.2015-0290MA.  3. Barosova H, Maione AG, Septiadi D, Sharma M, Haeni L, Balog S, O'Connell O, Jackson GR, Brown D, Clippinger AJ, Hayden P, Petri-Fink A, Stone V, Rothen-Rutishauser B. Use of EpiAlveolar Lung Model to Predict Fibrotic Potential of Multiwalled Carbon Nanotubes. ACS Nano. 2020 Apr 28;14(4):3941-3956. doi: 10.1021/acsnano.9b06860.  4. Behzadi S, Serpooshan V, Tao W, Hamaly MA, Alkawareek MY, Dreaden EC, Brown D, Alkilany AM, Farokhzad OC, Mahmoudi M. Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev. 2017 Jul 17;46(14):4218-4244. doi: 10.1039/c6cs00636a.  5. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007 Jan;81(1):1-5. doi: 10.1189/jlb.0306164.  6. Boyles MS, Young L, Brown DM, MacCalman L, Cowie H, Moisala A, Smail F, Smith PJ, Proudfoot L, Windle AH, Stone V. Multi-walled carbon nanotube induced frustrated phagocytosis, cytotoxicity and pro-inflammatory conditions in macrophages are length dependent and greater than that of asbestos. Toxicol In Vitro. 2015 Oct;29(7):1513-28. doi: 10.1016/j.tiv.2015.06.012. 7. Brown DM, Kinloch IA, Bangert U, Windle AH, Walter DM, Walker GS, et al. An in vitro study of the potential of carbon nanotubes and nanofibres to induce inflammatory mediators and frustrated phagocytosis. Carbon. 2007;45(9):1743-56. doi: https://doi.org/10.1016/j.carbon.2007.05.011. 8. Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. (2011). Current Intelligence Bulletin 62: Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research. Retrieved from https://www.cdc.gov/niosh/docs/2011-159/. 9. Cheng LC, Jiang X, Wang J, Chen C, Liu RS. Nano-bio effects: interaction of nanomaterials with cells. Nanoscale. 2013 May 7;5(9):3547-69. doi: 10.1039/c3nr34276j.  10. Clift MJ, Endes C, Vanhecke D, Wick P, Gehr P, Schins RP, Petri-Fink A, Rothen-Rutishauser B. A comparative study of different in vitro lung cell culture systems to assess the most beneficial tool for screening the potential adverse effects of carbon nanotubes. Toxicol Sci. 2014 Jan;137(1):55-64. doi: 10.1093/toxsci/kft216.  11. Decan N, Wu D, Williams A, Bernatchez S, Johnston M, Hill M, Halappanavar S. Characterization of in vitro genotoxic, cytotoxic and transcriptomic responses following exposures to amorphous silica of different sizes. Mutat Res Genet Toxicol Environ Mutagen. 2016 Jan 15;796:8-22. doi: 10.1016/j.mrgentox.2015.11.011. 12. Denholm EM, Phan SH. Bleomycin binding sites on alveolar macrophages. J Leukoc Biol. 1990 Dec;48(6):519-23. doi: 10.1002/jlb.48.6.519. 13. Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018 Mar 20;5:43. doi: 10.3389/fmed.2018.00043.  14. Di Paolo NC, Shayakhmetov DM. Interleukin 1α and the inflammatory process. Nat Immunol. 2016 Jul 19;17(8):906-13. doi: 10.1038/ni.3503. 15. Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, Remião F, Bastos ML, Carvalho F. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment. Crit Rev Toxicol. 2008;38(1):13-71. doi: 10.1080/10408440701669959. 16. Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol. 2010 Mar 22;7:5. doi: 10.1186/1743-8977-7-5. 17. Dörger M, Münzing S, Allmeling AM, Messmer K, Krombach F. Differential responses of rat alveolar and peritoneal macrophages to man-made vitreous fibers in vitro. Environ Res. 2001 Mar;85(3):207-14. doi: 10.1006/enrs.2001.4234. 18. Franks TJ, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Engelhardt J, Frid M, Herzog E, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, Serge J, Sunday ME, Voynow JA, Weinstein BM, Whitsett J, Williams MC. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function. Proc Am Thorac Soc. 2008 Sep 15;5(7):763-6. doi: 10.1513/pats.200803-025HR. 19. Kierdorf K, Prinz M, Geissmann F, Gomez Perdiguero E. Development and function of tissue resident macrophages in mice. Semin Immunol. 2015 Dec;27(6):369-78. doi: 10.1016/j.smim.2016.03.017. 20. Kim JE, Lim HT, Minai-Tehrani A, Kwon JT, Shin JY, Woo CG, Choi M, Baek J, Jeong DH, Ha YC, Chae CH, Song KS, Ahn KH, Lee JH, Sung HJ, Yu IJ, Beck GR Jr, Cho MH. Toxicity and clearance of intratracheally administered multiwalled carbon nanotubes from murine lung. J Toxicol Environ Health A. 2010;73(21-22):1530-43. doi: 10.1080/15287394.2010.511578.  21. Luettich K, Sharma M, Yepiskoposyan H, Breheny D, Lowe FJ. An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure. Front Toxicol. 2021 Dec 14;3:750254. doi: 10.3389/ftox.2021.750254. 22. Li XX, Jiang DY, Huang XX, Guo SL, Yuan W, Dai HP. Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice. Genet Mol Res. 2015 Dec 21;14(4):17391-8. doi: 10.4238/2015. 23. Matzinger P. The danger model: a renewed sense of self. Science. 2002 Apr 12;296(5566):301-5. doi: 10.1126/science.1071059. 24. Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1666-80. doi: 10.1164/ajrccm.157.5.9707141. 25. Murphy FA, Schinwald A, Poland CA, Donaldson K. The mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cells. Part Fibre Toxicol. 2012 Apr 3;9:8. doi: 10.1186/1743-8977-9-8.  26. Murthy S, Larson-Casey JL, Ryan AJ, He C, Kobzik L, Carter AB. Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure. FASEB J. 2015 Aug;29(8):3527-36. doi: 10.1096/fj.15-271304. 27. Nakayama M. Macrophage Recognition of Crystals and Nanoparticles. Front Immunol. 2018 Jan 29;9:103. doi: 10.3389/fimmu.2018.00103.  28. Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater. 2009 Jul;8(7):543-57. doi: 10.1038/nmat2442.  29. Neuhaus V, Schaudien D, Golovina T, Temann UA, Thompson C, Lippmann T, Bersch C, Pfennig O, Jonigk D, Braubach P, Fieguth HG, Warnecke G, Yusibov V, Sewald K, Braun A. Assessment of long-term cultivated human precision-cut lung slices as an ex vivo system for evaluation of chronic cytotoxicity and functionality. J Occup Med Toxicol. 2017 May 26;12:13. doi: 10.1186/s12995-017-0158-5. 30. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. 31. Padmore T, Stark C, Turkevich LA, Champion JA. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages. Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):58-67. doi: 10.1016/j.bbagen.2016.09.031. 32. Pascolo L, Gianoncelli A, Schneider G, Salomé M, Schneider M, Calligaro C, Kiskinova M, Melato M, Rizzardi C. The interaction of asbestos and iron in lung tissue revealed by synchrotron-based scanning X-ray microscopy. Sci Rep. 2013;3:1123. doi: 10.1038/srep01123.  33. Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008 Jul;3(7):423-8. doi: 10.1038/nnano.2008.111. 34. Rabolli V, Badissi AA, Devosse R, Uwambayinema F, Yakoub Y, Palmai-Pallag M, Lebrun A, De Gussem V, Couillin I, Ryffel B, Marbaix E, Lison D, Huaux F. The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles. Part Fibre Toxicol. 2014 Dec 13;11:69. doi: 10.1186/s12989-014-0069-x. 35. Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272. 36. Schinwald A, Donaldson K. Use of back-scatter electron signals to visualise cell/nanowires interactions in vitro and in vivo; frustrated phagocytosis of long fibres in macrophages and compartmentalisation in mesothelial cells in vivo. Part Fibre Toxicol. 2012 Aug 28;9:34. doi: 10.1186/1743-8977-9-34.  37. Suwara MI, Green NJ, Borthwick LA, Mann J, Mayer-Barber KD, Barron L, Corris PA, Farrow SN, Wynn TA, Fisher AJ, Mann DA. IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immunol. 2014 May;7(3):684-93. doi: 10.1038/mi.2013.87. 38. Varela JA, Bexiga MG, Åberg C, Simpson JC, Dawson KA. Quantifying size-dependent interactions between fluorescently labeled polystyrene nanoparticles and mammalian cells. J Nanobiotechnology. 2012 Sep 24;10:39. doi: 10.1186/1477-3155-10-39.  AOPWiki 2018-01-02T12:27:14

2023-05-17T15:10:26

Increased, secretion of proinflammatory mediators

Increased proinflammatory mediators

Cellular

Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. Pro-inflammatory mediators are secreted following exposure to an inflammogen in a gender/sex or developmental stage independent manner. They are secreted during inflammation in all species. Different types of pro-inflammatory mediators are secreted during innate or adaptive immune responses across various species (Mestas and Hughes, 2004). Cell-derived pro-inflammatory mediators include cytokines, chemokines, and growth factors. Blood derived pro-inflammatory mediators include vasoactive amines, complement activation products and others. These modulators can be grouped based on the cell type that secrete them, their cellular localisation and also based on the type of immune response they trigger. For example, members of the interleukin (IL) family including <a href="https://bioregistry.io/genecards:IL2">IL-2</a>, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>, <a href="https://bioregistry.io/genecards:IL7">IL-7</a>, <a href="https://bioregistry.io/genecards:IL9">IL-9</a>, <a href="https://bioregistry.io/genecards:IL15">IL-15</a>, <a href="https://bioregistry.io/genecards:IL21">IL-21</a>, <a href="https://bioregistry.io/genecards:IL3">IL-3</a>, <a href="https://bioregistry.io/genecards:IL5">IL-5</a> and Granulocyte-macrophage colony stimulating factor (<a href="https://bioregistry.io/genecards:CSF2">GM-CSF</a>) are involved in the adaptive immune responses. The pro-inflammatory cytokines include IL-1 family (<a href="https://bioregistry.io/genecards:IL1a">IL-1</a>α , <a href="https://bioregistry.io/genecards:IL1b">IL-1</a>β, <a href="https://bioregistry.io/genecards:IL1ra">IL-1r</a>α, <a href="https://bioregistry.io/genecards:IL18">IL-18</a>, <a href="https://bioregistry.io/genecards:IL36a">IL-36</a>α, <a href="https://bioregistry.io/genecards:IL36b">IL-36</a>β, <a href="https://bioregistry.io/genecards:IL36g">IL-36</a>γ, <a href="https://bioregistry.io/genecards:IL36Ra">IL-36R</a>α, <a href="https://bioregistry.io/genecards:IL37">IL-37</a>), <a href="https://bioregistry.io/genecards:IL6">IL-6 </a>family, Tumor necrosis factor (<a href="https://bioregistry.io/genecards:TNF">TNF</a>) family, <a href="https://bioregistry.io/genecards:IL17">IL-17</a>, and Interferon gamma (<a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ) (Turner et al., 2014). While <a href="https://bioregistry.io/genecards:IL4">IL-4</a> and <a href="https://bioregistry.io/genecards:IL5">IL-5</a> are considered T helper (Th) cell type 2 response, <a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ is suggested to be Th1 type response. Different types of pro-inflammatory mediators are secreted during innate or adaptive immune responses across various species (Mestas and Hughes, 2004). However, <a href="https://bioregistry.io/genecards:IL1">IL-1</a> family cytokines, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>, <a href="https://bioregistry.io/genecards:IL5">IL-5</a>, <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, <a href="https://bioregistry.io/genecards:TNFa">TNF</a>-α, IFN-γ are the commonly measured mediators in experimental animals and in humans. Similar gene expression patterns involving inflammation and matrix remodelling are observed in human patients of pulmonary fibrosis and mouse lungs exposed to bleomycin (Kaminski, 2002). Literature evidence for its perturbation: Several studies show increased proinflammatory mediators in rodent lungs and bronchoalveolar lavage fluid, and in cell culture supernatants following exposure to a variety of carbon nanotube (CNT) types and other materials. Poland et al., 2008 showed that long and thin CNTs (>5 µm) can elicit asbestos-like pathogenicity through the continual release of pro-inflammatory cytokines and reactive oxygen species. Exposure to crystalline silica induces release of inflammatory cytokines (TNF-α, IL-1, IL-6), transcription factors (Nuclear factor kappa B [NF-κB], Activator protein-1 [AP-1]) and kinase signalling pathways in mice that contain NF-κB luciferase reporter (Hubbard et al., 2002). Boyles et al., 2015 found that lung responses to long multi-walled carbon nanotubes (MWCNTs) included high expression levels of pro-inflammatory mediators Monocyte chemoattractant protein 1 (MCP-1), Transforming growth factor beta 1 (TGF-β1), and TNF-α (Boyles et al., 2015). Bleomycin administration in rodents induces lung inflammation and increased expression of pro-inflammatory mediators (Park et al., 2019). Inflammation induced by bleomycin, paraquat and CNTs is characterised by the altered expression of pro-inflammatory mediators. A large number of nanomaterials induce expression of cytokines and chemokines in lungs of rodents exposed via inhalation (Halappanavar et al., 2011; Husain et al., 2015a). Similarities are observed in gene programs involving pro-inflammatory event is observed in both humans and experimental mice (Zuo et al., 2002).

The selection of pro-inflammatory mediators for investigation varies based on the expertise of the lab, cell types studied and the availability of the specific antibodies. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) – will measure the abundance of cytokine mRNA in a given sample. The method involves three steps: conversion of RNA into cDNA by reverse transcription method, amplification of cDNA using the PCR, and the real-time detection and quantification of amplified products (amplicons) (Nolan et al., 2006). Amplicons are detected using fluorescence, increase in which is directly proportional to the amplified PCR product. The number of cycles required per sample to reach a certain threshold of fluorescence (set by the user – usually set in the linear phase of the amplification, and the observed difference in samples to cross the set threshold reflects the initial amount available for amplification) is used to quantify the relative amount in the samples. The amplified products are detected by the DNA intercalating minor groove-binding fluorophore SYBR green, which produces a signal when incorporated into double-stranded amplicons. Since the cDNA is single stranded, the dye does not bind enhancing the specificity of the results. There are other methods such as nested fluorescent probes for detection, but SYBR green is widely used. RT-PCR primers specific to several pro-inflammatory mediators in several species including mouse, rat and humans, are readily available commercially. Enzyme-linked immunosorbent assays (ELISA) – permit quantitative measurement of antigens in biological samples. The method is the same as described for the MIE. Both ELISA and qRT-PCR assays are used in vivo and are readily applicable to in vitro cell culture models, where cell culture supernatants or whole cell homogenates are used for ELISA or mRNA assays. Both assays are straight forward, quantitative and require relatively a small amount of input sample. Apart from assaying single protein or gene at a time, cytokine bead arrays or cytokine PCR arrays can also be used to detect a whole panel of inflammatory mediators in a multiplex method (Husain et al., 2015b). This method is quantitative and especially advantageous when the sample amount available for testing is scarce. Lastly, immunohistochemistry can also be used to detect specific immune cell types producing the pro-inflammatory mediators and its downstream effectors in any given tissue (Costa et al., 2017). Immunohistochemistry results can be used as weight of evidence; however, the technique is not quantitative and depending on the specific antibodies used, the assay sensitivity may also become an issue (Amsen and De Visser, 2009). Cell models - of varying complexity have been used to assess the expression of pro-inflammatory mediators. Two dimensional submerged monocultures of the main fibrotic effector cells – lung epithelial cells, macrophages, and fibroblasts – have routinely been used in vitro due to the large literature base, and ease of use, but do not adequately mimic the in vivo condition (Sharma et al., 2016; Sundarakrishnan et al., 2018). Recently, the EpiAlveolar in vitro lung model (containing epithelial cells, endothelial cells, and fibroblasts) was used to predict the fibrotic potential of MWCNTs, and researchers noted increases in the pro-inflammatory molecules TNF-α, IL-1β, and the pro-fibrotic TGF-β using ELISA (Barasova et al., 2020). A similar, but less complicated co-culture model of immortalized human alveolar epithelial cells and idiopathic pulmonary fibrosis patient derived fibroblasts was used to assess pro-fibrotic signalling, and noted enhanced secretion of Platelet derived growth factor (PDGF) and Basic fibroblast growth factor (bFGF), as well as evidence for epithelial to mesenchymal transition of epithelial cells in this system (Prasad et al., 2014). Models such as these better capitulate the in vivo pulmonary alveolar capillary, but have lower reproducibility as compared to traditional submerged mono-culture experiments.

Human, mouse, rat Cytokines are the common pro-inflammatory mediators secreted following inflammogenic stimuli. Cytokines can be defined as a diverse group of signaling protein molecules. They are secreted by different cell types in different tissues and in all mammalian species, irrespective of gender, age or sex. A lot of literature is available to support cross species, gender and developmental stage application for this KE. The challenge is the specificity; most cytokines exhibit redundant functions and many are pleotropic.

CL:0000255

CL eukaryotic cell

High Male High Female

High

Adults

High High High

1. Amsen D, de Visser KE, Town T. Approaches to determine expression of inflammatory cytokines. Methods Mol Biol. 2009;511:107-42. doi: 10.1007/978-1-59745-447-6_5.  2. Barosova H, Maione AG, Septiadi D, Sharma M, Haeni L, Balog S, O'Connell O, Jackson GR, Brown D, Clippinger AJ, Hayden P, Petri-Fink A, Stone V, Rothen-Rutishauser B. Use of EpiAlveolar Lung Model to Predict Fibrotic Potential of Multiwalled Carbon Nanotubes. ACS Nano. 2020 Apr 28;14(4):3941-3956. doi: 10.1021/acsnano.9b06860.  3. Boyles MS, Young L, Brown DM, MacCalman L, Cowie H, Moisala A, Smail F, Smith PJ, Proudfoot L, Windle AH, Stone V. Multi-walled carbon nanotube induced frustrated phagocytosis, cytotoxicity and pro-inflammatory conditions in macrophages are length dependent and greater than that of asbestos. Toxicol In Vitro. 2015 Oct;29(7):1513-28. doi: 10.1016/j.tiv.2015.06.012.  4. Costa PM, Gosens I, Williams A, Farcal L, Pantano D, Brown DM, Stone V, Cassee FR, Halappanavar S, Fadeel B. Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles. J Appl Toxicol. 2018 Mar;38(3):385-397. doi: 10.1002/jat.3548. 5. Halappanavar S, Jackson P, Williams A, Jensen KA, Hougaard KS, Vogel U, Yauk CL, Wallin H. Pulmonary response to surface-coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in microRNAs: a toxicogenomic study. Environ Mol Mutagen. 2011 Jul;52(6):425-39. doi: 10.1002/em.20639.  6. Hubbard AK, Timblin CR, Shukla A, Rincón M, Mossman BT. Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice. Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L968-75. doi: 10.1152/ajplung.00327.2001. 7. Husain M, Kyjovska ZO, Bourdon-Lacombe J, Saber AT, Jensen KA, Jacobsen NR, Williams A, Wallin H, Halappanavar S, Vogel U, Yauk CL. Carbon black nanoparticles induce biphasic gene expression changes associated with inflammatory responses in the lungs of C57BL/6 mice following a single intratracheal instillation. Toxicol Appl Pharmacol. 2015a Dec 15;289(3):573-88. doi: 10.1016/j.taap.2015.11.003. 8. Husain M, Wu D, Saber AT, Decan N, Jacobsen NR, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Intratracheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice. Nanotoxicology. 2015b;9(8):1013-22. doi: 10.3109/17435390.2014.996192. 9. Kaminski N. Microarray analysis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Suppl):S32-6. 10. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004 Mar 1;172(5):2731-8. doi: 10.4049/jimmunol.172.5.2731. 11. Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006;1(3):1559-82. doi: 10.1038/nprot.2006.236. 12. Park SJ, Im DS. Deficiency of Sphingosine-1-Phosphate Receptor 2 (S1P2) Attenuates Bleomycin-Induced Pulmonary Fibrosis. Biomol Ther (Seoul). 2019 May 1;27(3):318-326. doi: 10.4062/biomolther.2018.131. 13. Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008 Jul;3(7):423-8. doi: 10.1038/nnano.2008.111. 14. Prasad S, Hogaboam CM, Jarai G. Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair. Fibrogenesis Tissue Repair. 2014 Apr 29;7:7. doi: 10.1186/1755-1536-7-7.  15. Sharma M, Nikota J, Halappanavar S, Castranova V, Rothen-Rutishauser B, Clippinger AJ. Predicting pulmonary fibrosis in humans after exposure to multi-walled carbon nanotubes (MWCNTs). Arch Toxicol. 2016 Jul;90(7):1605-22. doi: 10.1007/s00204-016-1742-7.  16. Sundarakrishnan A, Chen Y, Black LD, Aldridge BB, Kaplan DL. Engineered cell and tissue models of pulmonary fibrosis. Adv Drug Deliv Rev. 2018 Apr;129:78-94. doi: 10.1016/j.addr.2017.12.013. 17. Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014 Nov;1843(11):2563-2582. doi: 10.1016/j.bbamcr.2014.05.014.  18. Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6292-7. doi: 10.1073/pnas.092134099. AOPWiki 2018-01-02T13:12:11

2023-05-17T15:18:03

Increased, recruitment of inflammatory cells

Recruitment of inflammatory cells

Tissue

Pro-inflammatory cells originate in bone marrow and are recruited to the site of infection or injury via circulation following specific pro-inflammatory mediator (cytokine and chemokine) signalling. Pro-inflammatory cells are recruited to lungs to clear the invading pathogen or the toxic substance. Monocytes (dendritic cells, macrophages, and neutrophils) are subsets of circulating white blood cells that are involved in the immune responses to pathogen or toxicant stimuli (Kolaczkowska and Kubes, 2013; Kopf et al., 2015). They are derived from the bone marrow. They can differentiate into different macrophage types and dendritic cells. They can be categorised based on their size, the type of cell surface receptors and their ability to differentiate following external or internal stimulus such as increased expression of cytokines. Monocytes participate in tissue healing, clearance of toxic substance or pathogens, and in the initiation of adaptive immunity. Recruited monocytes can also influence pathogenesis (Ingersoll et al., 2011). Sensing or recognition of pathogens and harmful substances results in the recruitment of monocytes to lungs (Shi and Pamer, 2011). Activated immune cells secrete a variety of pro-inflammatory mediators, the purpose of which is to propagate the immune signalling and response, which when not controlled, leads to chronic inflammation, cell death and tissue injury. Thus, Event 1496 and Event 1497 act in a positive feedback loop mechanism and propagate the proinflammatory environment. Literature evidence for its perturbation: Macrophages accumulate in bronchoalveolar fluid (BALF) post-exposure to bleomycin (Phan et al., 1980; Smith et al., 1995). Nanomaterial (NM)-induced inflammation is predominantly neutrophilic (Poulsen et al., 2015; Rahman L et al., 2017a; Rahman et al., 2017b; Shvedova et al., 2005). An increased number of neutrophils (Reynolds et al., 1977) is observed in the BALF of patients with idiopathic pulmonary fibrosis. Eosinophils are a type of white blood cells and a type of granulocytes (contain granules and enzymes) that are recruited following exposure to allergens, during allergic reactions such as asthma or during fibrosis (Reynolds et al., 1977). Multi-walled carbon nanotubes (MWCNTs) induce increased eosinophil count in lungs (Købler C et al., 2015). MWCNTs act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer et al., 2013). It is important to note that the stressor-induced Event 1495, Event 1496, and Event 1497 are part of the functional changes that we collectively consider as inflammation, and together, they mark the initiation of acute inflammatory phase. Event 1495 and Event 1496 occur at the cellular level. Event 1497 occurs at the tissue level.

In vivo, recruitment of pro-inflammatory cells is measured using BALF cellularity assay. The fluid lining the lung epithelium is lavaged (BALF) and its composition is assessed as marker of lung immune response to the toxic substances or pathogens. BALF is assessed quantitatively for types of infiltrating cells, levels and types of cytokines and chemokines. Thus, BALF assessment can aid in developing dose-response of a substance, to rank a substances’ potency and to set up no effect level of exposure for the regulatory decision making. For NMs, in vivo BALF assessment is recommended as a mandatory test (discussed in ENV/JM/MONO(2012)40 and also in OECD inhalation test guideline for NMs). Temporal changes in the BALF composition can be prognostic of initiation and progression of lung immune disease (Cho et al., 2010). In vitro, it is difficult to assess the recruitment of pro-inflammatory cells. Thus, a suit of pro-inflammatory mediators specific to cell types are assessed using the same techniques mentioned above (real-time reverse transcription-polymerase chain reaction [qRT-PCR], enzyme-linked immunosorbent assays [ELISA], immunohistochemistry) in cell culture models, as indicative of recruitment of cells into the lungs. Alternatively, the use of precision cut lung slices can allow for limited assessment of recruitment of tissue resident inflammatory cells, based on the repertoire of cells remaining in the specific slice following harvesting. This method was used to show that there is a histological increase in inflammatory foci following treatment with bleomycin and MWCNTs (Rahman et al., 2020). Finally, more complicated microfluidic lung-on-a-chip devices can be used to assess the migration of select immune cells and fibroblasts toward a simulated epithelium following treatment with a pro-fibrotic compound (He et al., 2017). However, this method is limited to two cell types, and it lacks the reservoirs of immune cells present in the body in vivo.

Human, mouse, rat

High Mixed

High

All life stages

High High High

1. Beamer CA, Girtsman TA, Seaver BP, Finsaas KJ, Migliaccio CT, Perry VK, Rottman JB, Smith DE, Holian A. IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology. 2013 Sep;7(6):1070-81. doi: 10.3109/17435390.2012.702230. 2. Cho WS, Duffin R, Poland CA, Howie SE, MacNee W, Bradley M, Megson IL, Donaldson K. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implications for nanoparticle testing. Environ Health Perspect. 2010 Dec;118(12):1699-706. doi: 10.1289/ehp.1002201.  3. He J, Chen W, Deng S, Xie L, Feng J, Geng J, et al. Modeling alveolar injury using microfluidic co-cultures for monitoring bleomycin-induced epithelial/fibroblastic cross-talk disorder. RSC Advances. 2017 7(68):42738-49. doi: 10.1039/C7RA06752F. 4. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 2011 Oct;32(10):470-7. doi: 10.1016/j.it.2011.05.001. 5. Købler C, Poulsen SS, Saber AT, Jacobsen NR, Wallin H, Yauk CL, Halappanavar S, Vogel U, Qvortrup K, Mølhave K. Time-dependent subcellular distribution and effects of carbon nanotubes in lungs of mice. PLoS One. 2015 Jan 23;10(1):e0116481. doi: 10.1371/journal.pone.0116481.  6. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013 Mar;13(3):159-75. doi: 10.1038/nri3399.  7. Kopf M, Schneider C, Nobs SP. The development and function of lung-resident macrophages and dendritic cells. Nat Immunol. 2015 Jan;16(1):36-44. doi: 10.1038/ni.3052. 8. Phan SH, Thrall RS, Ward PA. Bleomycin-induced pulmonary fibrosis in rats: biochemical demonstration of increased rate of collagen synthesis. Am Rev Respir Dis. 1980 Mar;121(3):501-6. doi: 10.1164/arrd.1980.121.3.501.  9. Poulsen SS, Saber AT, Williams A, Andersen O, Købler C, Atluri R, Pozzebon ME, Mucelli SP, Simion M, Rickerby D, Mortensen A, Jackson P, Kyjovska ZO, Mølhave K, Jacobsen NR, Jensen KA, Yauk CL, Wallin H, Halappanavar S, Vogel U. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol. 2015 Apr 1;284(1):16-32. doi: 10.1016/j.taap.2014.12.011.  10. Rahman L, Wu D, Johnston M, William A, Halappanavar S. Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. Mutagenesis. 2017a Jan;32(1):59-76. doi: 10.1093/mutage/gew048.  11. Rahman L, Jacobsen NR, Aziz SA, Wu D, Williams A, Yauk CL, White P, Wallin H, Vogel U, Halappanavar S. Multi-walled carbon nanotube-induced genotoxic, inflammatory and pro-fibrotic responses in mice: Investigating the mechanisms of pulmonary carcinogenesis. Mutat Res Genet Toxicol Environ Mutagen. 2017b Nov;823:28-44. doi: 10.1016/j.mrgentox.2017.08.005.  12. Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272.  13. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank MM, Crystal RG. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest. 1977 Jan;59(1):165-75. doi: 10.1172/JCI108615. 14. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10;11(11):762-74. doi: 10.1038/nri3070.  15. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, Tyurina YY, Gorelik O, Arepalli S, Schwegler-Berry D, Hubbs AF, Antonini J, Evans DE, Ku BK, Ramsey D, Maynard A, Kagan VE, Castranova V, Baron P. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L698-708. doi: 10.1152/ajplung.00084.2005.   16. Smith RE, Strieter RM, Zhang K, Phan SH, Standiford TJ, Lukacs NW, Kunkel SL. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol. 1995 May;57(5):782-7. doi: 10.1002/jlb.57.5.782.  AOPWiki 2018-01-03T09:31:07

2023-05-12T17:03:00

Increase, Cytotoxicity (epithelial cells)

Cellular

This key event is often associated with gavaged administration.

CL:0000066

CL epithelial cell

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:14

Increase, Reactive oxygen species

Increase, ROS

Cellular

Biological State: increased reactive oxygen species (ROS) Biological compartment: an entire cell -- may be cytosolic, may also enter organelles. Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017).  However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).  <div> Reactive oxygen species (ROS) refers to the chemical species superoxide, hydrogen peroxide, and their secondary reactive products. In the biological context, ROS are signaling molecules with important roles in cell energy metabolism, cell proliferation, and fate. Therefore, balancing ROS levels at the cellular and tissue level is an important part of many biological processes. Disbalance, mainly an increase in ROS levels, can cause cell dysfunction and irreversible cell damage. ROS are produced from both exogenous stressors and normal endogenous cellular processes, such as the mitochondrial electron transport chain (ETC). Inhibition of the ETC can result in the accumulation of ROS. Exposure to chemicals, heavy metal ions, or ionizing radiation can also result in increased production of ROS. Chemicals and heavy metal ions can deplete cellular antioxidants reducing the cell’s ability to control cellular ROS and resulting in the accumulation of ROS. Cellular antioxidants include glutathione (GSH), protein sulfhydryl groups, superoxide dismutase (SOD). ROS are radicals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010]. <Free oxygen radicals> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> superoxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> O2·- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> hydroxyl radical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ·OH </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitric oxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> NO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> organic radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> R· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> peroxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> alkoxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> thiyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RS· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> sulfonyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROS· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> thiyl peroxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RSOO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> disulfides </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RSSR </td> </tr> </tbody> </table> </div> <Non-radical ROS> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> hydrogen peroxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> H2O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> singlet oxygen </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> 1O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ozone/trioxygen </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O3 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> organic hydroperoxides </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROOH </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> hypochlorite </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ClO- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> peroxynitrite </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ONOO- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitrosoperoxycarbonate anion </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O=NOOCO2- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitrocarbonate anion </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O2NOCO2- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> dinitrogen dioxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> N2O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitronium </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> NO2+ </td> </tr> <tr> <td colspan="2" style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:580px"> highly reactive lipid- or carbohydrate-derived carbonyl compounds </td> </tr> </tbody> </table> </div> Potential sources of ROS include NADPH oxidase, xanthine oxidase, mitochondria, nitric oxide synthase, cytochrome P450, lipoxygenase/cyclooxygenase, and monoamine oxidase [Granger et al., 2015]. ROS are generated through NADPH oxidases consisting of p47phox and p67phox. ROS are generated through xanthine oxidase activation in sepsis [Ramos et al., 2018]. Arsenic produces ROS [Zhang et al., 2011]. Mitochondria-targeted paraquat and metformin mediate ROS production [Chowdhury et al., 2020]. ROS are generated by bleomycin [Lu et al., 2010]. Radiation induces dose-dependent ROS production [Ji et al., 2019]. ROS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation [Dickinson and Chang 2011; Egea et al. 2017]. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide (NO) is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. NO production is one of the main mechanisms by which phagocytes kill bacteria [Wang et al., 2017]. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes. ROS activity is principally local. Most ROS have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrite can survive long enough to diffuse across membranes [Calcerrada et al. 2011]. Consequently, local concentrations of ROS are much higher than average cellular concentrations, and signaling is typically controlled by colocalization with redox buffers [Dickinson and Chang 2011; Egea et al. 2017]. Although their existence is limited temporally and spatially, ROS interact with other ROS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase RNS. Both ROS and RNS also move into neighboring cells, and ROS can increase intracellular ROS signaling in neighboring cells [Egea et al. 2017]. In the primary event, photoreactive chemicals are excited by the absorption of photon energy.  The energy of the photoactivated chemicals transfer to oxygen and then generates the reactive oxygen species (ROS), including superoxide (O2−) via type I reaction and singlet oxygen (1O2) via type II reaction, as principal intermediate species in phototoxic reaction (Foote, 1991, Onoue et al. , 2009). </div>

Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies. Yuan, Yan, et al., (2013) described ROS monitoring by using H2-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H2-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm. Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013). Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS. On the basis of the pathogenesis of drug-induced phototoxicity, a reactive oxygen species (ROS) assay was proposed to evaluate the phototoxic risk of chemicals. The ROS assay can monitor generation of ROS, such as singlet oxygen and superoxide, from photoirradiated chemicals, and the ROS data can be used to evaluate the photoreactivity of chemicals (Onoue et al. , 2014, Onoue et al. , 2013, Onoue and Tsuda, 2006).  The ROS assay is a recommended approach by guidelines to evaluate the phototoxic risk of chemicals (ICH, 2014, PCPC, 2014). <div> <Direct detection> Many fluorescent compounds can be used to detect ROS, some of which are specific, and others are less specific. ・ROS can be detected by fluorescent probes such as p-methoxy-phenol derivative [Ashoka et al., 2020]. ・Chemiluminescence analysis can detect the superoxide, where some probes have a wider range for detecting hydroxyl radical, hydrogen peroxide, and peroxynitrite [Fuloria et al., 2021]. ・ROS in the blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020]. ・Hydrogen peroxide (H2O2) can be detected with a colorimetric probe, which reacts with H2O2 in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range. ・The levels of ROS can be quantified using multiple-step amperometry using a stainless steel counter electrode and non-leak Ag|AgCl reference node [Flaherty et al., 2017]. ・Singlet oxygen can be measured by monitoring the bleaching of p-nitrosodimethylaniline at 440 nm using a spectrophotometer with imidazole as a selective acceptor of singlet oxygen [Onoue et al., 2014]. <Indirect Detection> Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione [Dickinson and Chang 2011; Wang et al. 2013; Griendling et al. 2016]. However, these methods cannot generally distinguish between the oxidative species behind the changes and cannot provide good resolution for the kinetics of oxidative activity. </div>

ROS is a normal constituent found in all organisms, lifestages, and sexes.

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific High Mixed

High

All life stages

High Moderate Moderate Moderate High High High

Akai, K., et al. (2004). "Ability of ferric nitrilotriacetate complex with three pH-dependent conformations to induce lipid peroxidation." Free Radic Res. Sep;38(9):951-62. doi: 10.1080/1071576042000261945 Ashoka, A. H., et al. (2020). "Recent Advances in Fluorescent Probes for Detection of HOCl and HNO." ACS omega, 5(4), 1730-1742. doi:10.1021/acsomega.9b03420 B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534 Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313. Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85. Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659. Calcerrada, P., et al. (2011). "Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications." Curr Pharm Des 17(35): 3905-3932. Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76. Chowdhury, A. R., et al. (2020). "Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon." Redox Biol. doi: 10.1016/j.redox.2020.101606. PMID: 32604037; PMCID: PMC7327929. Dickinson, B. C. and Chang C. J. (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511. Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81. Egea, J., et al. (2017). "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)." Redox biology 13: 94-162. Flaherty, R. L., et al. (2017). "Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer." Breast Cancer Research, 19(1), 1–13. https://doi.org/10.1186/s13058-017-0823-8 Foote CS. Definition of type I and type II photosensitized oxidation. Photochem Photobiol. 1991;54:659. Fuloria, S., et al. (2021). "Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer." Antioxidants (Basel, Switzerland) 10(1) 128. doi:10.3390/antiox10010128 Go, Y. M. and Jones, D. P. (2013). "The redox proteome." J Biol Chem 288(37): 26512-26520. Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304. Granger, D. N. and Kvietys, P. R. (2015). "Reperfusion injury and reactive oxygen species: The evolution of a concept" Redox Biol. doi: 10.1016/j.redox.2015.08.020. PMID: 26484802; PMCID: PMC4625011. Griendling, K. K., et al. (2016). "Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association." Circulation research 119(5): e39-75. Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75. ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014. Itziou, A., et al. (2011). "In vivo and in vitro effects of metals in reactive oxygen species production, protein carbonylation, and DNA damage in land snails Eobania vermiculata." Archives of Environmental Contamination and Toxicology, 60(4), 697–707. https://doi.org/10.1007/s00244-010-9583-5 Ji, W. O., et al. "Quantitation of the ROS production in plasma and radiation treatments of biotargets." Sci Rep. 2019 Dec 27;9(1):19837. doi: 10.1038/s41598-019-56160-0. PMID: 31882663; PMCID: PMC6934759. Kruk, J. and Aboul-Enein, H. Y. (2017). "Reactive Oxygen and Nitrogen Species in Carcinogenesis: Implications of Oxidative Stress on the Progression and Development of Several Cancer Types." Mini-Reviews in Medicinal Chemistry, 17:11. doi:10.2174/1389557517666170228115324 Lee, D. Y., et al. (2020). "PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood." Theranostics, 10(5), 1997-2007. doi:10.7150/thno.39662 Li, Z., et al. (2020). "Inhibition of MiR-25 attenuates doxorubicin-induced apoptosis, reactive oxygen species production and DNA damage by targeting pten." International Journal of Medical Sciences, 17(10), 1415–1427. https://doi.org/10.7150/ijms.41980 Liou, G. Y. and Storz, P. "Reactive oxygen species in cancer." Free Radic Res. 2010 May;44(5):479-96. doi:10.3109/10715761003667554. PMID: 20370557; PMCID: PMC3880197. Lu, Y., et al. (2010). "Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production." American journal of respiratory cell and molecular biology, 42(4), 432–441. https://doi.org/10.1165/rcmb.2009-0002OC Onoue, S., et al. (2013). "Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation." J Appl Toxicol. 33(11):1241-50. doi: 10.1002/jat.2776. Epub 2012 Jun 13. PMID: 22696462. Onoue S, Hosoi K, Toda T, Takagi H, Osaki N, Matsumoto Y, et al. Intra-/inter-laboratory validation study on reactive oxygen species assay for chemical photosafety evaluation using two different solar simulators. Toxicology in vitro : an international journal published in association with BIBRA. 2014;28:515-23. Onoue S, Hosoi K, Wakuri S, Iwase Y, Yamamoto T, Matsuoka N, et al. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation. Journal of applied toxicology : JAT. 2013;33:1241-50. Onoue S, Kawamura K, Igarashi N, Zhou Y, Fujikawa M, Yamada H, et al. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates. J Pharm Biomed Anal. 2008;47:967-72. Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early in vitro identification of phototoxic potential of new drug entities in drug discovery and development. Current drug safety. 2009;4:123-36. Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64. Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen. Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier. PCPC. PCPC 2014 safety evaluation guidelines; Chapter 7: Evaluation of Photoirritation and Photoallergy potential. Personal Care Products Council; 2014. Ramos, M. F. P., et al. (2018). "Xanthine oxidase inhibitors and sepsis." Int J Immunopathol Pharmacol. 32:2058738418772210. doi:10.1177/2058738418772210 Ravanat, J. L., et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715. Schutzendubel, A. and Polle, A. (2002). "Plant responses to abiotic stresses: heavy metal-induced oxidative stress and protection by mycorrhization." Journal of Experimental Botany, 53(372), 1351–1365. https://doi.org/10.1093/jexbot/53.372.1351 Seto Y, Kato M, Yamada S, Onoue S. Development of micellar reactive oxygen species assay for photosafety evaluation of poorly water-soluble chemicals. Toxicology in vitro : an international journal published in association with BIBRA. 2013;27:1838-46. Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31. Silva, R., et al. (2019). "Light exposure during growth increases riboflavin production, reactive oxygen species accumulation and DNA damage in Ashbya gossypii riboflavin-overproducing strains." FEMS Yeast Research, 19(1), 1–7. https://doi.org/10.1093/femsyr/foy114 Tsuchiya K, et al. (2005). "Oxygen radicals photo-induced by ferric nitrilotriacetate complex." Biochim Biophys Acta. 1725(1):111-9. doi:10.1016/j.bbagen.2005.05.001 Wang, J., et al. (2017). "Glucocorticoids Suppress Antimicrobial Autophagy and Nitric Oxide Production and Facilitate Mycobacterial Survival in Macrophages." Scientific reports, 7(1), 982. https://doi.org/10.1038/s41598-017-01174-9 Wang, X., et al. (2013). "Imaging ROS signaling in cells and animals." Journal of molecular medicine 91(8): 917-927. Yen, Cheng Chien, et al. "Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway." Archives of toxicology 85 (2011): 565-575. Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330. Zhang, Z., et al. (2011). "Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. " Toxicology and Applied Pharmacology, 256(2), 114-121. doi:10.1016/j.taap.2011.07.016 AOPWiki 2016-11-29T18:41:29

2025-06-12T01:27:08

Secondary genotoxicity

Cellular

AOPWiki 2022-05-25T05:25:49

2022-05-25T05:25:49

Increased, DNA damage and mutation

Cellular

DNA damages are alteration of the DNA backbone including abasic site, single or double strand breaks or inter-strand crosslinks. These damages could be recognized and repaired by specialized enzymes. However, if damages persist, mutation in the DNA sequences can occur. Unlike DNA damages, DNA mutations when both strands are modified cannot be repaired and are heritable. Mutations affect the genotype and could affect phenotype. Different mechanisms are implicated in DNA damage such as oxidative burst, DNA repair dysfunction or centrosome amplification and chromosome instability [1].

DNA damages could be measured using different assays, such as micronucleus formation (OECD n°487) [2], comet assay with different protocols for the detection of double and single-strand breaks, DNA-DNA and DNA-protein crosslinks, adduct and oxidized nucleotides (OECD n°489) [3, 4] and γH2AX for the analysis of DNA strand breaks [5]. DNA mutation could be analyzed with Ames test or via the analysis of frequencies of mutations (OECD n°471) [6].

The DNA damages and mutations can occur in mammals, male or female, and is generally measured in adults.

Not Specified Unspecific

Not Specified

Adult

Not Specified

1.         Zhang Y. Cell toxicity mechanism and biomarker. 2018;7 1:34; doi: 10.1186/s40169-018-0212-7. 2.         Kato T, Totsuka Y, Ishino K, Matsumoto Y, Tada Y, Nakae D, et al. Genotoxicity of multi-walled carbon nanotubes in both in vitro and in vivo assay systems. Nanotoxicology. 2013;7 4:452-61; doi: 10.3109/17435390.2012.674571. 3.         Pacurari M, Yin XJ, Zhao J, Ding M, Leonard SS, Schwegler-Berry D, et al. Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells. 2008;116 9:1211-7; doi: 10.1289/ehp.10924. 4.         Hiraku Y, Guo F, Ma N, Yamada T, Wang S, Kawanishi S, et al. Multi-walled carbon nanotube induces nitrative DNA damage in human lung epithelial cells via HMGB1-RAGE interaction and Toll-like receptor 9 activation. Particle and fibre toxicology. 2016;13:16; doi: 10.1186/s12989-016-0127-7. 5.         Catalan J, Siivola KM, Nymark P, Lindberg H, Suhonen S, Jarventaus H, et al. In vitro and in vivo genotoxic effects of straight versus tangled multi-walled carbon nanotubes. Nanotoxicology. 2016;10 6:794-806; doi: 10.3109/17435390.2015.1132345.            6.         Fukai E, Sato H, Watanabe M, Nakae D, Totsuka Y. Establishment of an in vivo simulating co-culture assay            platform for genotoxicity of multi-walled carbon nanotubes. Cancer science. 2018; doi: 10.1111/cas.13534. AOPWiki 2019-07-03T11:49:50

2019-08-13T05:41:05

Increase, Cell Proliferation

Cellular

Throughout their life, cells replicate their organelles and genetic information before dividing to form two new daughter cells, in a process known as cellular proliferation. This replicative process is known as the cell cycle and is subdivided into various stages notably, G1, S, G2, and M in mammals. G1 and G2 are gap phases, separating mitosis and DNA synthesis. Differentiated cells typically remain in G1; however, quiescent cells reside in an optional phase just before G1, known as G0.   Progression through the cycle is dependent on sufficient nutrient availability to provide optimal nucleic acid, protein, and lipid levels, as well as sufficient cell mass. To this end, the cell cycle is mediated by three major checkpoints: the restriction (R) point, or G1/S checkpoint, controlling entry into S phase, the G2/M checkpoint, controlling entry into mitosis, and one more controlling entry into cytokinesis. If conditions are ideal for division, cells will pass the restriction point (G1/S) and begin the activation and expression of genes used for duplicating centrosomes and DNA, eventually leading to proliferation (Cuyàs et al., 2014).   Various protein complexes, known as cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) regulate passage through each phase by activating and inhibiting specific processes (Lovicu et al., 2014). The CDKs are responsible for controlling progression through the cell cycle. They promote DNA synthesis and mitosis, and therefore cell division (Barnum & O’Connell, 2014). Furthermore, growth factors are required to stimulate cell division, but after passing through the restriction point at G1 they are no longer necessary (Lovicu et al., 2014).   In the context of cancer, one hallmark is the sustained and uncontrolled cell proliferation (Hanahan et al., 2011, Portt et al., 2011). When cells obtain a growth advantage due to mutations in critical genes that regulate cell cycle progression, they may begin to proliferate excessively, resulting in hyperplasia and potentially leading to the development of a tumor. This is often achieved through oncogene activation and inactivation of tumor suppressor genes (Hanahan et al., 2011). Cell inactivation and the replacement of these cells can initiate clonal expansion (Heidenreich and Paretzke et al., 2008).  Sustained atrophy/degeneration olfactory epithelium under the influence of a cytotoxic agent leads to adaptive tissue remodeling. Cell types unique to olfactory epithelium, e.g. olfactory neurons, sustentacular cells and Bowmans glands, are replaced by cell types comprising respiratory epithelium or squamous epithelium.

Two common methods of measuring cell proliferation in vivo are the use of Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) labeling (Pera, 1977), and Ki67 immunostaining (Grogan, 1988). BrdU is a synthetic analogue of the nucleoside Thymidine. BrDu is incorporated into DNA synthesized during the S1 phase of cell replication and is stable for long periods. Labeling of dividing cells by BrdU is accomplished by infusion, bolus injection, or implantation of osmotic pumps containing BrdU for a period of time sufficient to generate measureable numbers of labeled cells. Tissue sections are stained immunhistochemically with antibodies for BrdU and labeled cells are counted as dividing cells. Similarly, 5-iodo-2'-deoxyuridine (IdU) is another analogue of thymidine used to measure cell proliferation as it is also incorporated into DNA during its synthesis (Devine & Behbehani, 2021). Ki67 is a cellular marker of replication not found in quiescent cells (Roche, 2015). Direct immunohistochemical staining of cells for protein Ki67 using antibodies is an alternative to the use of BrdU, with the benefit of not requiring a separate treatment (injection for pulse-labeling). Cells positive for Ki67 are counted as replicating cells. Replicating cell number is reported per unit tissue area or per cell nuclei (Bogdanffy, 1997). Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed. <table border="1" cellpadding="1" cellspacing="1" style="height:298px; width:595px"> <tbody> <tr> <td style="background-color:#dddddd; text-align:center">Assay Name</td> <td style="background-color:#dddddd; text-align:center">References</td> <td style="background-color:#dddddd; text-align:center">Description</td> <td style="background-color:#dddddd; text-align:center">OECD Approved Assay</td> </tr> <tr> <td>CyQuant Cell Proliferation Assay</td> <td>Jones et al., 2001</td> <td>DNA-binding dye is added to cell cultures, and the dye signal is measured directly to provide a cell count and thus an indication of cellular proliferation</td> <td>N/A</td> </tr> <tr> <td>Nucleotide Analog Incorporation Assays (e.g. BrdU, EdU)</td> <td>Romar et al., 2016, Roche; 2013</td> <td>Nucleoside analogs are added to cells in culture or injected into animals and become incorporated into the DNA at different rates, depending on the level of cellular proliferation; Antibodies conjugated to a peroxidase or fluorescent tag are used for quantification of the incorporated nucleoside analogs using techniques such as ELISA, flow cytometry, or microscopy</td> <td>Yes (No. 442B)</td> </tr> <tr> <td>Cytoplasmic Proliferation Dye Assays</td> <td>Quah & Parish, 2012</td> <td>Cells are incubated with a cytoplasmic dye of a certain fluorescent intensity; Cell divisions decrease the intensity in such a way that the number of divisions can be calculated using flow cytometry measurements</td> <td>N/A</td> </tr> <tr> <td>Colourimetric Dye Assays</td> <td>Vega-Avila & Pugsley, 2011; American Type Culture Collection</td> <td>Cells are incubated with a dye that changes colour following metabolism; Colour change can be measured and extrapolated to cell number and thus provide an indication of cellular proliferation rates</td> <td>N/A</td> </tr> <tr> <td>BrdU, Ki67, IdU Quantification - Flow Cytometry </td> <td>Ligasová et al., 2017; Devine & Behehani, 2021; Kim & Sederstrom, 2015</td> <td>Measurement of cell proliferation biomarkers by flow cytometry, normalized to total levels of BrdU, Ki67 or IdU.   </td> <td>No</td> </tr> </tbody> </table>

Cell proliferation is a central process supporting development, tissue homeostasis and carcinogenesis, each of which occur in all vertebrates. This key event has been observed nasal tissues of rats exposed to the chemical initiator vinyl acetate. In general, cell proliferation is necessary in the biological development and reproduction of most organisms. This KE is thus relevant and applicable to all multicellular cell types, tissue types, and taxa. Life stage applicability: This key event is not life stage specific (Fujimichi and Hamada, 2014; Barnard et al., 2022). Sex applicability: This key event is not sex specific (Markiewicz et al., 2015). Evidence for perturbation by a stressor: There is a large body of evidence supporting the effectiveness of ionizing radiation, UV, and mechanical wounding as stressors for increased cell proliferation. These stressors can be subdivided into X-rays (van Sallmann, 1951; Ramsell and Berry, 1966; Richards, 1966; Riley et al., 1988; Riley et al., 1989; Kleiman et al., 2007; Pendergrass et al., 2010; Fujimichi and Hamada, 2014, Markiewicz et al., 2015; Bahia et al., 2018), 60Co γ-rays (Hanna and O’Brien, 1963; Barnard et al., 2022; McCarron et al., 2021), 137Cs γ-rays (Andley and Spector, 2005), neutrons (Richards, 1966; Riley et al., 1988; Riley et al., 1989), 40Ar (Worgul et al., 1986), 56Fe (Riley et al., 1989), UVB (Söderberg et al., 1986; Andley et al., 1994; Cheng et al., 2019), UVC (Trenton and Courtois, 1981), and mechanical wounding (Riley et al., 1989).

High Unspecific

High

All life stages

High High High

Andley, U. P. et al. (1994), “Modulation of lens epithelial cell proliferation by enhanced prostaglandin synthesis after UVB exposure”, Investigative Ophthalmology & Visual Science, Vol. 35/2, Rockville, pp. 374-381   Andley, U. and A. Spector (2005), “Peroxide resistance in human and mouse lens epithelial cell lines is related to long-term changes in cell biology and architecture”, Free Radical Biology & Medicine, Vol. 39/6, Elsevier B.V, United States, https://doi.org/10.1016/j.freeradbiomed.2005.04.028  Bahia, S. et al. (2018), “Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays”, International journal of radiation biology, Vol. 94/4, England, <a href="https://doi.org/10.1080/09553002.2018.1439194" rel="noreferrer noopener" target="_blank">https://doi.org/10.1080/09553002.2018.1439194</a>  Barnard, S. et al. (2022), “Lens Epithelial Cell Proliferation in Response to Ionizing Radiation.”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, <a href="https://doi.org/10.1667/RADE-20-00294.1" rel="noreferrer noopener" target="_blank">https://doi.org/10.1667/RADE-20-00294.1</a>  Barnum, K. and M. O’Connell (2014), “Cell cycle regulation by checkpoints”, in Cell cycle control, Springer, New York, http://doi.org/ 10.1007/978-1-4939-0888-2  Bogdanffy. et al. (1997). “FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM”, Inhalation Toxicology, Taylor & Francis. 9: 331-350. Cheng, T. et al. (2019), “lncRNA H19 contributes to oxidative damage repair in the early age-related cataract by regulating miR-29a/TDG axis”, Journal of cellular and molecular medicine, Vol. 23/9, Wiley Subscription Services, Inc. England, https://doi.org/10.1111/jcmm.14489  Cuyàs, E. et al. (2014), “Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway”, in Cell cycle control, Springer, New York, http://dx.doi.org/ 10.1007/978-1-4939-0888-2  Devine,R. D, and G. K. Behbehani (2021), “Use of the Pyrimidine Analog, 5-Iodo-2'-Deoxyuridine (IdU) with Cell Cycle Markers to establish Cell Cycle Phases in a Mass Cytometry Platform”, Journal of visualized experiments. (176). doi:10.3791/60556   Fujimichi, Y. and N. Hamada (2014), “Ionizing irradiation not only inactivates clonogenic potential in primary normal human diploid lens epithelial cells but also stimulates cell proliferation in a subset of this population”, PloS one, Vol. 9/5, e98154, Public Library of Science, United States, <a href="https://doi.org/10.1371/journal.pone.0098154" rel="noreferrer noopener" target="_blank">https://doi.org/10.1371/journal.pone.0098154</a>  Grogan. et al. (1988). “Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67”, Blood. 71: 1157-1160. Hanna, C. and J. E. O’Brien (1963), “Lens epithelial cell proliferation and migration in radiation cataracts”, Radiation research, Academic Press, Inc, United States, <a href="https://doi.org/10.2307/3571405" rel="noreferrer noopener" target="_blank">https://doi.org/10.2307/3571405</a>  Hanahan, D. & R. A. Weinberg, (2011),” Hallmarks of cancer: the next generation”, Cell. 144(5):646-74. doi: 10.1016/j.cell.2011.02.013. Heidenreich WF, Paretzke HG. (2008) Promotion of initiated cells by radiation-induced cell inactivation. Radiat Res. Nov;170(5):613-7. doi: 10.1667/RR0957.1. PMID: 18959457. Jones, J. L. et al. (2001), Sensitive determination of cell number using the CyQUANT cell proliferation assay. Journal of Immunological Methods. 254(1-2), 85-98. Doi:10.1016/s0022-1759(01)00404-5. Kim, K. H. and Sederstrom J. M. (2015), “Assaying Cell Cycle Status Using Flow Cytometry.” Current protocols in molecular biology, 111:28.6.1-28.6.11., doi:10.1002/0471142727.mb2806s111   Kleiman, N. J. et al. (2007), “Mrad9 and Atm haplinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice”, Radiation research, Vol. 168/5, Radiation Research Society, United States, <a href="https://doi.org/10.1667/rr1122.1" rel="noreferrer noopener" target="_blank">https://doi.org/10.1667/rr1122.1</a>  Ligasová, A. et al. (2017), “Cell cycle profiling by image and flow cytometry: The optimised protocol for the detection of replicational activity using 5-Bromo-2'-deoxyuridine, low concentration of hydrochloric acid and exonuclease III.” PloS one, 12(4): e0175880, doi:10.1371/journal.pone.0175880   Lovicu, J. et al (2014), “Lens epithelial cell proliferation”, in Lens epithelium and posterior capsular opacification, Springer, Tokyo, http://dx.doi.org/ 10.1007/978-4-431-54300-8_4  Markiewicz, E. et al. (2015), “Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin K1 expression and lens shape”, Open biology, Vol. 5/4, The Royal Society, England, <a href="https://doi.org/10.1098/rsob.150011" rel="noreferrer noopener" target="_blank">https://doi.org/10.1098/rsob.150011</a>  McCarron, R. A. et al. (2021), “Radiation-induced lens opacity and cataractogenesis: a lifetime study using mice of varying genetic backgrounds”, Radiation research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00266.1  Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular vision, Vol. 16, Molecular Vision, United States, pp. 1496-1513  Pera, Mattias and Detzer (1977). “Methods for determining the proliferation kinetics of cells by means of 5-bromodeoxyuridine”, Cell Tissue Kinet.10: 255-264. Doi: 10.1111/j.1365-2184.1977.tb00293.x. Portt, L. et al. (2011), “Anti-apoptosis and cell survival: a review”, Biochim Biophys Acta. 21813(1):238-59. doi: 10.1016/j.bbamcr.2010.10.010. Quah, J. C. B. & R. C. Parish (2012), “New and improved methods for measuring lymphocyte proliferation in vitro and in vivo using CFSE-like fluorescent dyes”, Journal of Immunological Methods. 379(1-2), 1-14. doi: 10.1016/j.jim.2012.02.012. Ramsell, T. G. and R. J. Berry (1966), “Recovery from X-ray damage to the lens. The effects of fractionated X-ray doses observed in rabbit lens epithelium irradiated in vivo”, British Journal of Radiology, Vol. 39/467, England, pp. 853-858  Riley, E. F. et al. (1988), “Recovery of murine lens epithelial cells from single and fractionated doses of X rays and neutrons”, Radiation Research, Vol. 114/3, Academic Press Inc, Oak Brook, https://doi.org/10.2307/3577127  Riley, E. F. et al. (1989), “Comparison of recovery from potential mitotic abnormality in mitotically quiescent lens cells after X, neutron, and 56Fe irradiations”, Radiation Research, Vol. 119/2, United States, pp. 232-254  Richards, R. D. (1966), “Changes in lens epithelium after X-ray or neutron irradiation (mouse and rabbit)”, Transactions of the American Ophthalmological Society, Vol. 64, United States, pp. 700-734  Roche Applied Science, (2013), “Cell Proliferation Elisa, BrdU (Colourmetric) ». Version 16 Romar, A. G., S. T. Kupper & J. S. Divito (2015), “Research Techniques Made Simple: Techniques to Assess Cell Proliferation”,  Journal of Investigative Dermatology. 136(1), e1-7. doi: 10.1016/j.jid.2015.11.020. Söderberg, P. G. et al. (1986), “Unscheduled DNA synthesis in lens epithelium after in vivo exposure to UV radiation in the 300 nm wavelength region”, Acta Ophthalmologica, Vol. 64/2, Blackwell Publishing Ltd, Oxford, UK, https://doi.org/10.1111/j.1755-3768.1986.tb06894.x  Trenton, J. A. and Y. Courtois (1981), “Evolution of the distribution, proliferation and ultraviolet repair capacity of rat lens epithelial cells as a function of maturation and aging”, Mechanisms of Ageing and Development, Vol. 15/3, Elsevier, Ireland, https://doi.org/1016/0047-6374(81)90134-2  Vega-Avila, E. & K. M. Pugsley (2011), “An Overview of Colorimetric Assay Methods Used to Assess Survival or Proliferation of Mammalian Cells”, Proc. West. Pharmacol. Soc. 54, 10-4. von Sallmann, L. (1951), “Experimental studies on early lens changes after x-ray irradiation III. Effect of X-radiation on mitotic activity and nuclear fragmentation of lens epithelium in normal and cysteine-treated rabbits”, Transactions of the American Ophthalmological Society, Vol. 48, United States, pp. 228-242  Worgul, B. V. et al. (1986), “Accelerated heavy particles and the lens II. Cytopathological changes”, Investigative Ophthalmology and Visual Science, Vol 27/1, pp. 108-114  AOPWiki 2016-11-29T18:41:27

2024-12-10T15:01:01

Lung cancer

Organ

Lung cancer is one of the most prevalent cancer in the world. This cancer occur mainly at the level of bronchial cells and affect more rarely at the level of alveoli. Lung cancer affects more men rather than women because of tabacco consumption (trend is reversing). This disease is at the first place on terms of mortality due to the late detection (Cancer League, WHO).

Lung cancer can be measured in human by analysis of the sputum cytology, the chest X-ray and all the techniques usually used in this medical field. In animal experiments, the OECD guidelines n°451 provide the procedure for the study of carcinogenesis development.

Lung cancer can occur in mammals, male or female, generally in adults

Not Specified Unspecific

Not Specified

Adult

Not Specified

AOPWiki 2019-07-03T11:51:27

2019-08-13T05:34:23

<upstream-id>aa9150f8-c4c1-436c-971d-ccfa9ec530fc</upstream-id> <downstream-id>8e83fa25-f390-47fb-a33e-2b3b4535b22a</downstream-id> Innate immune response is the first line of defence in any organism against invading infectious pathogens and toxic substances. It involves tissue triggered startle response to cellular stress and is described by a complex set of interactions between the toxic stimuli, soluble macromolecules and cells (reviewed in Nathan, 2002). The process culminates in a functional change defined as inflammation, purpose of which is to resolve infection and promote healing. In lungs, the interaction of toxic substances with resident cells results in cellular stress, death or necrosis (Pouwels et al., 2016) leading to release of intracellular components such as alarmins (Damage associated molecular patterns [DAMPs], Interleukin (IL)-1α, High mobility group box 1 [HMGB1]). Released alarmins (danger sensors) bind cell surface receptors such as Interleukin 1 Receptor 1 (IL-1R1), Toll Like Receptors (TLRs) or others leading to activation of innate immune response signalling. For example, binding of IL-1α to IL-1R1 can release Nuclear factor kappa B (NF-κB) resulting in its translocation to nucleus and transactivation of pro-inflammatory genes including cytokines, growth factors and acute phase genes. The signalling also stimulates secretion of a variety of pro-inflammatory mediators. Overexpression of IL-1α in cells induces increased secretion of pro-inflammatory mediators. Products of necrotic cells are shown to stimulate the immune system in an IL-1R1-dependent manner (Chen et al., 2007). The secreted alarmins activate resident cells pre-stationed in the tissues such as mast cells or macrophages leading to propagation of the already initiated immune response by releasing more eicosanoids, cytokines, chemokines and other pro-inflammatory mediators. Thus, secreted mediators signal the recruitment of neutrophils, which are the first cell types to be recruited in acute inflammatory conditions. Neutrophil influx in sterile inflammation is driven mainly by IL-1α (Rider P, 2011). IL-1 mediated signalling regulates neutrophil influx in silica-induced acute lung inflammation (Hornung et al., 2008). IL-1 signalling also mediates neutrophil influx in other tissues and organs including liver and peritoneum. Other types of cells including macrophages, eosinophils, and lymphocytes are also recruited in a signal-specific manner. Recruitment of leukocytes induces critical cytokines associated with the T helper type 2 immune response, including Tumor necrosis factor alpha (TNF-α), IL-1β, and IL-13.

The biological plausibility of this relationship is high. There is a mechanistic relationship between the MIE (Event 1495) and KE1 (Event 1496) which has been evidenced in a number of both in vitro and in vivo model systems in response to stressors such as, asbestos, silica, bleomycin, carbon nanotubes, and metal oxide nanoparticles (NPs) (Behzadi et al., 2017; Denholm & Phan 1990; Dostert et al., 2008; Mossman & Churg 1998). Increased expression of IL-1α or IL-1β following lung exposure to multi-walled carbon nanotubes (MWCNTs), bleomycin, micro silica particles, silica crystals, and polyhexamethylene guanidine phosphate has been shown to be associated with neutrophil influx in rodents (Gasse et al., 2007; Girtsman et al., 2014; Hornung et al., 2008; Nikota et al., 2017; Rabolli et al., 2014; Suwara et al., 2014). Inhibition of IL-1 function by knocking out the expression of IL-1R1 using IL-1R1 knockout mice or via treatment with IL-1α or IL-1β neutralising antibodies results in complete abrogation of lung neutrophilic influx following exposure to MWCNTs (Nikota et al, 2017), cigarette smoke (CS) (Halappanavar et al., 2013), silica crystals (Rabolli et al., 2014) and bleomycin (Gasse et al., 2007). IL1-R1, Myeloid differentiation primary response protein (Myd88) or the IL-33/St2 signaling are involved in pulmonary fibrosis induced by bleomycin (Gasse et al., 2007; Xu et al., 2016).

Empirical support for this KER is moderate. There are limited in vitro studies, which show a temporal and dose-dependent relationship between these two events, using the upregulation of specific surface receptors as a proxy for direct membrane interaction (Chan et al., 2018; Denholm & Phan, 1990; Roy et al., 2014). There are also studies that provide general support for the idea that an interaction with the lung resident cell membrane components leads to increased, secretion of pro-inflammatory and pro-fibrotic mediators (<a href="https://aopwiki.org/system/dragonfly/production/2023/05/17/rd7q13ywo_MIE_KE1_Table_1.pdf">Table 1</a>). Dose-Response Evidence: There are a few studies which provide evidence for a dose-response relationship in this KER. An in vitro study demonstrated a concentration-response relationship, in which silica exposure induced increases in pro-inflammatory cytokines through scavenger receptors in cultured bone marrow-derived murine mast cells. Cells were exposed to 6.25, 12.5, 25 or 50 µg/cm2 silica dioxide (SiO2) for 24 h. Macrophage scavenger receptor (MSR2) expression increased over time at 50 µg/cm2 and in a concentration-dependent relationship. Moreover, Tumor necrosis factor alpha (TNF-α), IL-13 and Monocyte chemoattractant protein-1 (MCP-1) increased in a concentration-dependent manner (Brown et al., 2007). This provides indications that at higher concentrations of the stressor, the interaction with the lung resident cell membrane components (Event 1495) leads to an increased secretion of pro-inflammatory mediators (Event 1496). Temporal Evidence: In vitro and in vivo studies have demonstrated temporal concordance of the KEs. TLR4 signal pathway was evaluated in differentiated macrophages exposed to silica at 2.5 µg/cm2. After 16 and 24 h, the mRNA expression level of TLR4 increased. Moreover, the protein expression level of TLR-4 and related MyD88/Toll-interleukin-1 receptor domain containing adaptor protein (TIRAP) pathway increased at 24 h. Release of  IL-1β, IL-6, IL-10, and TNF-α was induced by silica exposure at 24 h. Pre-treatment with resatorvid (TAK-242), an inhibitor of TLR4 signaling, suppressed the release of the cytokines (Chan et al., 2018). Macrophages exposed to zinc oxide (ZnO) NPs at 2.5 µg/mL for 24 h increased the expression level of TLR6 and MyD88, TNF receptor-associated factor (TRAF), and IL-1 receptor-associated kinase (IRAK). At 24 h, they also observed an increase in the mRNA and protein levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. These results demonstrated that ZnO NPs induced pro-inflammatory mediators by TLR stimulation and Mitogen-activated protein kinases (MAPKs) activation (Roy et al., 2014). The pro-inflammatory IL-1β induced granulocyte migration and can be produced as a result of cellular detection of pathogen associated molecular patterns (PAMPs). Mice exposed to 2.5 mg/mouse of silica by instillation showed an increase of mRNA expression of pro-IL-1β in bronchoalveolar lavage fluid (BALF) at 6, 12, and 24 h post-exposure in a time-dependent manner. At early time points (1 h, 3 h, 6 h), there was an increase in the release of an alarmin (IL-1α) which indicates that the alarmin was released due to cell damage leading to cytokine production and an inflammatory reaction. Moreover, at 24 h, the levels of mature IL-1β and neutrophil accumulation in BALF increased. Neutralization or deletion of IL-1α reduced the observed responses (Rabolli et al., 2014). Epithelial damage can lead to the release of alarmins. In this stead, conditioned media from primary human bronchial epithelial cells (PBECs) exposed to thapsigargin was able to induce a pro-inflammatory response in primary human lung fibroblasts. PBECs were exposed to thapsigargin (a tumor promoter in mammalian cells) 20 µM for 2 h. After that, the cell culture medium was replaced, and cells were incubated for 24 h. At this time, the medium was recovered and used to culture lung fibroblast for 5 h. This conditioned media from epithelial cell damage contains the alarmin IL-1α, which induced increased gene expression of IL-6, IL-8, MCP-1, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) in fibroblasts. These responses were reduced with anti-IL-1α treatment (Suwara et al., 2014). Heijink et al. 2015 conducted a similar strategy to identify the relationship between DAMPs and pro-inflammatory mediator release after exposure to CS. Neutrophils treated with CS bubbled for 1 min, released high levels of HMGB1 as a consequence of necrotic cell death. The cell-free supernatant, which contains HMGB1, was used to culture human bronchial epithelial cells, and after 24 h it promoted the production of the C-X-C motif chemokine ligand (CXCL)8 or IL-8 by lung epithelial cells. Pharmacological inhibitors, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC) and Receptor for advanced glycation endproducts (RAGE) antagonist peptide (RAP), reduced the effect of CXCL8 release. HMGB1 and Heat shock protein 70 (HSP-70) can be released by damaged hepatocytes. In a study, mice were treated with acetaminophen 350 mg/Kg for 3 and 6 h. At these time points, the liver perfusate was obtained and an increase in HSP-70 and HMGB1 protein levels was observed. RAW 264.7 cells (a macrophage cell line) treated with the liver perfusate exhibited increased mRNA expression levels of MCP-1 and IL-1β (Martin-Murphy et al. 2010). Female mice were intratracheally administered with bleomycin at 5 mg/kg to represent idiopathic pulmonary fibrosis. IL-33, a molecule that can act as a DAMP, increased in lungs after 3 and 7 days of treatment. In serum, at 7-, 14- and 28-days post-exposure, IL-4 and IL-13 increased. It was concluded that IL-33/ST2 signaling pathway is involved in pulmonary fibrosis by bleomycin (Xu et al., 2016).

Attenuation or complete abrogation of KE1 (Event 1496) and KE2 (Event 1497) following inflammogenic stimuli is observed in rodents lacking functional IL-1R1 or other cell surface receptors that engage innate immune response upon stimulation. However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNTs was suppressed at 24 h in mice deficient in IL-1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving DAMPs is fundamental for survival, which may necessitate activation of compensatory signaling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response.

A majority of the in vivo studies are conducted with only one dose and thus, it is difficult to derive quantitative dose-response relationships based on the existing data. However, it is clear from the studies referenced above that greater concentrations or doses of pro-fibrotic substances result in higher release of alarmins, and consequently, higher pro-inflammatory signalling. The above studies also demonstrate strong temporal relationships between the individual KEs.

One study has demonstrated a response-response relationship for this KER. Human intervertebral disc cells were treated with 0, 0.5, 1, or 2 mg/ml of recombinant HMGB1 for 24 h. Protein levels were determined in cell medium supernatant by enzyme-linked immunosorbent assay (ELISA). HMGB1 stimulates the expression of IL-6 and Matrix metalloproteinase 1 (MMP-1) in a response-response relationship. A strong correlation was observed by Spearman’s rank correlation coefficient between HMGB1 treatment and IL-6 or MMP-1 levels (Shah et al., 2019). Other reports have studied both KEs, but they do not indicate if the response-response relationship was linear or not (coefficient or correlation is not shown) (Chakraborty et al., 2017; Fukuda et al. 2017; Kim et al., 2020, Piazza et al., 2013; Yang et al., 2012;).

Some studies have described how long after a change in the MIE (Event 1495; interaction substance and components), KE1 (Event 1496; pro-inflammatory mediators are secreted) is impacted (Table 2). Table 2. Time-scale related studies relevant to the MIE (Event 1495) - KE1 (Event 1496) relationship. <table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:584px"> <tbody> <tr> <td rowspan="2" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:30px; vertical-align:top; width:85px"> Reference </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:30px; vertical-align:top; width:122px"> In vitro/in vivo/population study </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:30px; vertical-align:top; width:145px"> Design </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:30px; vertical-align:top; width:127px">   MIE (Event 1495) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:30px; vertical-align:top; width:105px"> KE1 (Event 1496) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:30px; vertical-align:top; width:127px"> Timepoint </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:30px; vertical-align:top; width:105px"> Timepoint </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:85px"> Xu et al., 2016 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:122px"> In vivo </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:145px"> 40 Female Kunming strain mice Bleomycin was intratracheally administered 5 mg/Kg. Days post-exposure </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:127px"> IL-33 3, 7 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:105px"> IL-4, IL-13 7, 14, and 28 days </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:57px; vertical-align:top; width:85px"> Roy et al., 2014 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:57px; vertical-align:top; width:122px"> In vitro </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:57px; vertical-align:top; width:145px"> Primary mice macrophages exposed to 2.5 mg/ml ZnO for 24 hrs. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:57px; vertical-align:top; width:127px"> Increased TLR6 expression 0.5, 3, 6, 12, and 24 h </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:57px; vertical-align:top; width:105px"> Increased IL-6, TNF-α  24 h </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:89px; vertical-align:top; width:85px"> Rabollli et al., 2014 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:89px; vertical-align:top; width:122px"> In vivo </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:89px; vertical-align:top; width:145px"> Female C57BL/6 mice Exposed to silica 2.5 mg/mouse by instillation   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:89px; vertical-align:top; width:127px"> Increased the release of IL-1α  1, 3, and 6 h </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:89px; vertical-align:top; width:105px"> Increased mRNA expression of pro-IL-1β  6, 12, and 24 h </td> </tr> </tbody> </table>

Pancreatic cancer cells stimulated with S100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A9 (S100A9) released pro-inflammatory cytokines IL-8, TNF-α, and Fibroblast growth factor (FGF). Cancer cell-derived conditioned media and the individual cytokines (TNF-α and Transforming growth factor beta [TGF-β]) induced the protein expression of S100A8 and S100A9 in HL-60 monocytic cell line and primary human monocytes (Nedjadi et al. 2018).

High Male High Female

High

All life stages

High High

The activation of the immune response after interacting with pathogens or toxic substances is present in all species, irrespective of age or sex.

<ol> <li style="text-align:justify"> Behzadi S, Serpooshan V, Tao W, Hamaly MA, Alkawareek MY, Dreaden EC, Brown D, Alkilany AM, Farokhzad OC, Mahmoudi M. Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev. 2017 Jul 17;46(14):4218-4244. doi: 10.1039/c6cs00636a.  </li> <li style="text-align:justify"> Brown JM, Swindle EJ, Kushnir-Sukhov NM, Holian A, Metcalfe DD. Silica-directed mast cell activation is enhanced by scavenger receptors. Am J Respir Cell Mol Biol. 2007 Jan;36(1):43-52. doi: 10.1165/rcmb.2006-0197OC.  </li> <li style="text-align:justify"> Chakraborty D, Zenker S, Rossaint J, Hölscher A, Pohlen M, Zarbock A, Roth J, Vogl T. Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner. Front Immunol. 2017 Nov 13;8:1493. doi: 10.3389/fimmu.2017.01493. </li> <li style="text-align:justify"> Chan JYW, Tsui JCC, Law PTW, So WKW, Leung DYP, Sham MMK, Tsui SKW, Chan CWH. Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis. Int J Med Sci. 2018 Jun 14;15(10):986-991. doi: 10.7150/ijms.24715.  </li> <li style="text-align:justify"> Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007 Jul;13(7):851-6. doi: 10.1038/nm1603.  </li> <li style="text-align:justify"> Denholm EM, Phan SH. Bleomycin binding sites on alveolar macrophages. J Leukoc Biol. 1990 Dec;48(6):519-23. doi: 10.1002/jlb.48.6.519. </li> <li style="text-align:justify"> Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008 May 2;320(5876):674-7. doi: 10.1126/science.1156995.  </li> <li style="text-align:justify"> Fukuda K, Ishida W, Miura Y, Kishimoto T, Fukushima A. Cytokine expression and barrier disruption in human corneal epithelial cells induced by alarmin released from necrotic cells. Jpn J Ophthalmol. 2017 Sep;61(5):415-422. doi: 10.1007/s10384-017-0528-7. </li> <li style="text-align:justify"> Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007 Dec;117(12):3786-99. doi: 10.1172/JCI32285.  </li> <li style="text-align:justify"> Girtsman TA, Beamer CA, Wu N, Buford M, Holian A. IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57Bl/6 mice. Nanotoxicology. 2014 Feb;8(1):17-27. doi: 10.3109/17435390.2012.744110. </li> <li style="text-align:justify"> Halappanavar S, Nikota J, Wu D, Williams A, Yauk CL, Stampfli M. IL-1 receptor regulates microRNA-135b expression in a negative feedback mechanism during cigarette smoke-induced inflammation. J Immunol. 2013 Apr 1;190(7):3679-86. doi: 10.4049/jimmunol.1202456. </li> <li style="text-align:justify"> Heijink IH, Pouwels SD, Leijendekker C, de Bruin HG, Zijlstra GJ, van der Vaart H, ten Hacken NH, van Oosterhout AJ, Nawijn MC, van der Toorn M. Cigarette smoke-induced damage-associated molecular pattern release from necrotic neutrophils triggers proinflammatory mediator release. Am J Respir Cell Mol Biol. 2015 May;52(5):554-62. doi: 10.1165/rcmb.2013-0505OC.  </li> <li style="text-align:justify"> Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008 Aug;9(8):847-56. doi: 10.1038/ni.1631. </li> <li style="text-align:justify"> Kim DH, Gu A, Lee JS, Yang EJ, Kashif A, Hong MH, Kim G, Park BS, Lee SJ, Kim IS. Suppressive effects of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma. Int J Med Sci. 2020 Feb 4;17(4):498-509. doi: 10.7150/ijms.37833.  </li> <li> Martin-Murphy BV, Holt MP, Ju C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett. 2010 Feb 15;192(3):387-94. doi: 10.1016/j.toxlet.2009.11.016. </li> <li> Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1666-80. doi: 10.1164/ajrccm.157.5.9707141. </li> <li style="text-align:justify"> Nathan C. Points of control in inflammation. Nature. 2002 Dec 19-26;420(6917):846-52. doi: 10.1038/nature01320.  </li> <li style="text-align:justify"> Nedjadi T, Evans A, Sheikh A, Barerra L, Al-Ghamdi S, Oldfield L, Greenhalf W, Neoptolemos JP, Costello E. S100A8 and S100A9 proteins form part of a paracrine feedback loop between pancreatic cancer cells and monocytes. BMC Cancer. 2018 Dec 17;18(1):1255. doi: 10.1186/s12885-018-5161-4.  </li> <li style="text-align:justify"> Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. </li> <li style="text-align:justify"> Piazza O, Leggiero E, De Benedictis G, Pastore L, Salvatore F, Tufano R, De Robertis E. S100B induces the release of pro-inflammatory cytokines in alveolar type I-like cells. Int J Immunopathol Pharmacol. 2013 Apr-Jun;26(2):383-91. doi: 10.1177/039463201302600211. </li> <li style="text-align:justify"> Pouwels SD, Zijlstra GJ, van der Toorn M, Hesse L, Gras R, Ten Hacken NH, Krysko DV, Vandenabeele P, de Vries M, van Oosterhout AJ, Heijink IH, Nawijn MC. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L377-86. doi: 10.1152/ajplung.00174.2015.  </li> <li style="text-align:justify"> Rabolli V, Badissi AA, Devosse R, Uwambayinema F, Yakoub Y, Palmai-Pallag M, Lebrun A, De Gussem V, Couillin I, Ryffel B, Marbaix E, Lison D, Huaux F. The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles. Part Fibre Toxicol. 2014 Dec 13;11:69. doi: 10.1186/s12989-014-0069-x. </li> <li> Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, White MR, Dinarello CA, Apte RN. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. 2011 Nov 1;187(9):4835-43. doi: 10.4049/jimmunol.1102048.  </li> <li style="text-align:justify"> Roy R, Singh SK, Das M, Tripathi A, Dwivedi PD. Toll-like receptor 6 mediated inflammatory and functional responses of zinc oxide nanoparticles primed macrophages. Immunology. 2014 Jul;142(3):453-64. doi: 10.1111/imm.12276. </li> <li style="text-align:justify"> Shah BS, Burt KG, Jacobsen T, Fernandes TD, Alipui DO, Weber KT, Levine M, Chavan SS, Yang H, Tracey KJ, Chahine NO. High mobility group box-1 induces pro-inflammatory signaling in human nucleus pulposus cells via toll-like receptor 4-dependent pathway. J Orthop Res. 2019 Jan;37(1):220-231. doi: 10.1002/jor.24154.  </li> <li style="text-align:justify"> Suwara MI, Green NJ, Borthwick LA, Mann J, Mayer-Barber KD, Barron L, Corris PA, Farrow SN, Wynn TA, Fisher AJ, Mann DA. IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immunol. 2014 May;7(3):684-93. doi: 10.1038/mi.2013.87. </li> <li style="text-align:justify"> Xu J, Zheng J, Song P, Zhou Y, Guan S. IL‑33/ST2 pathway in a bleomycin‑induced pulmonary fibrosis model. Mol Med Rep. 2016 Aug;14(2):1704-8. doi: 10.3892/mmr.2016.5446. </li> <li style="text-align:justify"> Yang D, Postnikov YV, Li Y, Tewary P, de la Rosa G, Wei F, Klinman D, Gioannini T, Weiss JP, Furusawa T, Bustin M, Oppenheim JJ. High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses. J Exp Med. 2012 Jan 16;209(1):157-71. doi: 10.1084/jem.20101354. </li> </ol> AOPWiki 2018-01-05T13:18:17

2025-02-20T07:12:34

<upstream-id>aa9150f8-c4c1-436c-971d-ccfa9ec530fc</upstream-id> <downstream-id>85c86a3d-fe90-4d1c-9a6b-df8deace1bb5</downstream-id>

AOPWiki 2022-05-25T05:44:42

2022-05-25T05:44:42

<upstream-id>8e83fa25-f390-47fb-a33e-2b3b4535b22a</upstream-id> <downstream-id>446e191c-ec98-47d1-abc6-84ee49609a6c</downstream-id> Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. They are secreted following inflammation or exposure to an inflammogen. Commonly measured pro-inflammatory mediators include Interleukin (IL)-1 family cytokines, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>,<a href="https://bioregistry.io/genecards:IL5"> IL-5</a>, <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, Tumor necrosis factor alpha (<a href="https://bioregistry.io/genecards:TNFa">TNF</a>-α), Interferon gamma (<a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ) (<a href="https://aopwiki.org/events/1496">KE1496</a>) Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Hofman et al., 2016). With more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells (Villeneuve et al., 2018). Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.

The biological plausibility of this KER is high. There are very well established functional relationships between the secreted signalling molecules and the chemotactic effects on pro-inflammatory cells (Harris, 1954; Petri and Sanz 2018). Increased proinflammatory mediators means more pro-inflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villeneuve et al., 2018). Increased signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophils (Khatri et al., 2017; Leick et al., 2014; Marchini et al., 2016). The leukocytes will differentiate into mature pro-inflammatory cells, in response to mediators they encounter in the local tissue microenvironment (Villeneuve et al., 2018). With higher levels of leukocytes from increased pro-inflammatory mediators, it causes an increase in pro-inflammatory cells (Libby, 2015).

The empirical support for this KER is moderate. There are many studies which show temporal and dose-dependent recruitment of immune cells following increases in pro-inflammatory mediators. However, these mediators exhibit pleiotropy, and knockdown or knockout of a single pathway or mediator can result in compensation and recruitment of immune cells at a later time, as is seen in Nikota et al.,. 2017. (Chen et al., 2016; Nikota et al., 2017; Schremmer et al., 2016) (Additional studies available in <a href="https://aopwiki.org/system/dragonfly/production/2023/05/15/352dxc9mru_KE1_KE2_Table_1.pdf">Table 1</a>). Dose-Response Evidence: Many studies provide dose-response evidence of this KER. For example, in vitro and in vivo studies testing stressors at different doses/concentrations have demonstrated a dose-response relationship; at the higher dose of the stressor, the pro-inflammatory mediators increased, leading to an increase of pro-inflammatory cell recruitment.  Ma et al. (2016) studied inflammatory responses in male BALB/c mice exposed to multi-walled carbon nanotubes (MWCNTs) administered intravenously at different doses (0.5-4 mg/kg) for 2 days. A dose-dependent relationship was found between the levels of the inflammatory mediators IL-6 and TNF-α and the MWCNT dose. At the highest dose, 4 mg/Kg, white blood cells, lymphocytes, and neutrophils levels increased. Porter et al. (2020) have demonstrated that MWCNTs caused dose-dependent and time-dependent pulmonary inflammation in male C57BL/6J mice. Animals received a single dose of 2.5, 10, or 40 µg/mouse. At 40 µg/mouse, IL-1β and IL-18 increased at one day post-exposure. Moreover, polymorphonuclear leukocytes increased on day 1, and after 7 days the number of inflammatory cells was higher. Zinc oxide (ZnO) nanoparticles (NPs) can induce metal fume fever and acute inflammation. Female C57BL/6J mice were intratracheally instilled once at 11, 33, and 100 µg/kg with coated ZnO NPs. Inflammatory responses were evaluated after 1, 3, and 28 days of exposure. An increase in Serum Amyloid A3 (Saa3) mRNA in lung tissue was observed at 33 and 100 µg/kg. Neutrophils accumulated in bronchoalveolar lavage fluid (BALF) after 28 days of exposure in a dose-dependent manner (Hadrup et al., 2019). Polyhexamethylene guanidine phosphate (PHMG-P) is used as a disinfectant. PHMG-P at 0.3, 0.9, and 1.5 mg/kg was instilled into the lungs of mice. At 7- and 14-days post-exposure an increase in the levels of pro-inflammatory markers (IL-1β, IL-6, and C-X-C motif chemokine ligand [CXCL]1) and an increase in mRNA levels of Monocyte chemoattractant protein (MCP)1, Matrix metalloproteinase (MMP)2, and MMP12 was seen. Moreover, on day 7, neutrophils were recruited to the inflamed site. These changes were observed in a dose-response manner (Song et al., 2014). Bourdon et al. 2012 evaluated the toxicity of carbon black nanoparticles (CBNPs) in mouse lung and liver. C57BL/6 mice were exposed to Printex 90 CBNPs with 0.018, 0.054, or 0.162 mg, and after 1, 3, and 28 days of the single instillation, BALF was analyzed. Polymorphonuclear cell counts in BALF increased in a dose-dependent manner with the strongest recruitment 1- and 3-days post-exposure and remained elevated at day 28. CBNPs also increased the expression of Saa3 mRNA levels in lung tissue on days 1, 3, and 28 in a dose-dependent manner. Although this response decreased over time, the expression of Saa3 mRNA increased at all time points, which indicates a persistent acute phase response. A study evaluated the mechanisms of toxicity after exposure to particulate matter (PM2.5) in a tri-culture system: A549 cells (alveolar epithelial cells) and THP-1 differentiated macrophages in the apical chamber; meanwhile, EA.hy926 endothelial cells were cultured in the basolateral chamber. The system was exposed to PM2.5 at three different concentrations 20, 60, and 180 µg/ml for 24 h. An increase in the pro-inflammatory mediators IL-6, IL-8, and TNF-α was observed, as well an increase in mRNA expression of MMP9, Intercellular adhesion molecule 1 (ICAM-1), and caveolin 1 (CAV-1). These genes are involved in the movement and recruitment of leukocytes in sites of inflammation. Changes were observed in a concentration-dependent manner (Wang et al., 2019). In another study, female C57BL/6 mice were exposed to 18, 54, or 162 µg of MWCNT/mouse via single intratracheal instillation. An increased gene expression of Cxcl1, IL-6, Metallothionein-2 (Mt2), Saa1, and Saa2 was observed in a dose-dependent manner at 24 h post-exposure. Moreover, an increase in the recruitment of pro-inflammatory cells was observed in a dose-dependent manner (Poulsen et al., 2013). Temporal Evidence: There is significant evidence of the temporal relationship between the two KES.  In vitro and in vivo studies have demonstrated that pro-inflammatory mediators (Event 1496) increased prior to the recruitment of pro-inflammatory cells (Event 1497). Female C57BL/6J mice were exposed to carbon NPs at 20 µg/mouse via intratracheal instillation. An increase in the levels of cytokines CXCL1, CXCL2, and CXCL5 at 3 h post-exposure was observed, with peaks after 12 and 18 h post-exposure. These pro-inflammatory mediators preceded neutrophil recruitment (12 and 24 h post-exposure) (Chen et al., 2016). Alveolar macrophages (AM) were isolated from lungs 3 to 12 h after instillation, but they did not show a pro-inflammatory response. The authors suggest that AM are not involved in the initiation of the inflammatory response. Meanwhile, alveolar epithelial type II cells induced the highest CXCL levels and acute neutrophilic inflammation. Nickel oxide (NiO) NPs intratracheally instilled at one single dose 200 cm2/rat into female Wistar rats induced an increase of pro-inflammatory cytokines in BALF, at 24 and 74 h for Cytokine-Induced neutrophil chemoattractant 3 (CINC-3) and eotaxin, respectively. At 24 h and 48 h, neutrophils were observed, and after 72 h, the levels of neutrophils, eosinophils, and macrophages increased (Lee et al., 2016). Porter et al. (2002) have shown pulmonary inflammation in rats exposed to crystalline silica aerosol at a concentration of 15 mg/m3 (6h/day, 5 days/week) for 116 days.  Lung disease was linked to TNF-α and IL-10 production in a timely response (10-116 days). The number of polymorphonuclear cells in the BALF increased progressively from day 41 - 116. One study has demonstrated a dose-response and temporal relationship for these two KEs (Patowary et al., 2020). Female Wistar rats were exposed to oleoresin capsicum sprays at 2, 6, and 10%, and after 1, 3, and 24 h post-exposure, blood cell and BALF cytokines were evaluated. The pro-inflammatory cytokine TNF-α increased in a dose-dependent manner, and polymorphonuclear cells increased in a time-dependent manner. Schremmer et al. (2016) have reported the time course of chemotaxis in vitro in response to the challenge of biopersistent particles and their relation to inflammatory mediators.  NR8383 rat alveolar macrophages were challenged with different types of particles for 1, 4, and 16 h. The cell supernatants obtained from different time points were used to evaluate the chemotaxis of unexposed NR8383 macrophages. They found that nanosized silica at 16 µg/cm2 induced an elevated transcription of C-C motif chemokine ligand (CCL)4, CXCL1, CXCL3, and TNF-α in a time-dependent manner. The pro-inflammatory cytokines present in the supernatants induced chemotaxis of unexposed macrophages at 4 and 16 h post-exposure. Husain et al. (2015) found increased expression of genes related to chemotactic recruitment of pro-inflammatory cells at 3 h and 1 day after exposure to 162 µg/mouse CBNPs in female C57BL/6 mice. They observed an increase in the gene expression of pro-inflammatory mediators at day 1 (CXCL2, Ccl2), day 3 (IL-17, IL-33), day 14 (Cd2), and day 42 (Cxcl) post-exposure. The KE2 (Event 1497) increased over time with the maximum levels of neutrophils, macrophages, eosinophils, and lymphocytes at 4- and 5-days post-exposure. This response suggests chronic inflammation occurs because of an incomplete resolution of acute inflammation. Rahman et al. (2017) evaluated whether different titanium dioxide (TiO2) NPs induce lung inflammation. C57BL/6 mice were exposed to 18, 54, 162, or 486 µg/mouse of TiO2 NPs via single intratracheal instillation. At 1-day post-exposure, gene expression analysis showed more changes in genes associated with inflammation and fibrosis. Moreover, after 1- and 28 days post-exposure, an increase in cell counts in BALF was observed in a dose-dependent manner. Ho et al. (2013) evaluated the inflammatory response in mice exposed to coated quantum dots, cadmium-based NPs, (QD705-poly(ethylene glycol[PEG], QD705-COOH) at 12 or 60 µg/mouse. At 2-, 17- and 90-days post-exposure, an increase in the level of TNF-α, IL-1b, IL-6, CXCL1, CCL2, CCL1, CCL17, and CXCL13 mRNA levels in lungs was observed and the amount of polymorphonuclear cells in BALF increased in a dose-dependent manner at day 7 post-exposure. The inflammatory response increased on days 2 and 17, but on day 90 decreased. QD705-COOH induced granulomas persistently presented from 2 to 90 days. Morimoto et al. (2010) examined the different kinds of cytokines related to lung inflammation by NiO exposure. Rats were intratracheally exposed to 0.33 mg/Kg and 0.66 mg/kg NiO NPs and were sacrificed at day 3, after 1 week, 1, 3, and 6 months post-exposure. Infiltration of alveolar macrophages in lung tissue and BALF was observed from day 3 to 3 months post-exposure, with higher levels after 1 and 3 months. Before the recruitment of inflammatory cells, an increase in the level of pro-inflammatory cells such as MCP-1 and IL-1β in BALF was observed. NiO NPs induced a persistent inflammatory effect. Kamata et al. (2011) studied the impact of CBNPs on susceptible subjects with predisposing lung disease and the effects of nanoparticles on inflammation and fibrotic changes. To achieve this goal, female C57BL/6J mice were intratracheally administered with bleomycin 20 µg/mouse and CBNPs 10 µg/mouse. Evaluations were performed post-exposure at different time points. An increase of IL-6 and CCL2 in BALF was observed at days 2 and 7. After 7- and 14 days, a recruitment of pro-inflammatory cells was observed. Oxidant injury (evaluated as nitrotyrosine expression) was observed after 7 days and 14 days. The levels of Transforming growth factor beta (TGF-β) increased over time with the highest level at day 14. Finally, they observed an increase in lung collagen deposition and a decrease in lung compliance at day 21.

Attenuation or complete abrogation of KE1 (<a href="https://aopwiki.org/events/1496">KE1496</a>) and KE2 (<a href="https://aopwiki.org/events/1497">KE1497</a>) following inflammogenic stimuli is observed in rodents lacking functional Interleukin 1 receptor type 1 (IL-1R1) or other cell surface receptors that engage innate immune response upon stimulation (Gasse et al., 2007; Halappanavar et al., 2013). However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNTs was suppressed at 24 h in mice deficient in IL-1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving damage-associated molecular patterns is fundamental for survival, which may necessitate activation of compensatory signalling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response. Most of the studies evaluate one dose at different time points or one-time point at different concentrations. Moreover, some studies have demonstrated that a stressor can lead to the recruitment of pro-inflammatory cells, but the presence of pro-inflammatory mediators was not determined (Westphal et al., 2015). Recruitment of pro-inflammatory cells is a key event that is complicated to replicate in vitro conditions as cell migration is induced by cooperative chemotactic mediators (Gouwy et al., 2015) which are produced and released from different cells. Therefore, more kinetics studies in co-culture techniques are needed to fill this gap.

<table border="1" bordercolor="#ccc" cellpadding="5" cellspacing="0" class="table table-bordered table-fullwidth" style="border-collapse:collapse"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> <tr> <th> </th> <th> </th> <th> </th> <th> </th> </tr> <tr> <th> Air pollution </th> <th> </th> <th> Air pollution primes immunity; increases the levels of circulating IL-1β, IL-6 and TNF-α; impairs the normal functions of macrophages and alveolar cells. Exposure to particulate air pollution, such as PM2.5, is associated with pulmonary inflammation [1,2]. Both short term and chronic exposures to fine particulate matter (PM) have been shown to increase levels of circulating IL-1β, IL-6 and TNF-α [3-5]. Air pollution works as a priming factor that exacerbates the inflammatory phenotype of COVID-19 and further dysregulates immune cell activity. Dysregulation of the immune cell functions, on the other hand, plays a role in tissue damage and the ability of the immune system to fight pathogens, which increases the susceptibility to concomitant bacterial superinfection, for instance [6-9]. </th> <th style="text-align:justify"> [1] Zhao et al., 2013 [2] Jia et al., 2021 [3] Tsai et al., 2012 [4] Ljungman et al., 2009 [5] Kido et al., 2011 [6] Knoll et al., 2021 [7] Glencross et al., 2020 [8] Yamasaki and Eeden, 2018 9) Signorini et al., 2018 </th> </tr> </thead> <tbody> <tr> <td> Chemicals (weak evidence) </td> <td> Per- and polyfluoroalkyl substances (PFAS) (Perfluorooctane sulfonate [PFOS], perfluorooctanoic acid [PFOA], perfluorobutane sulfonic acid [PFBS], perfluorooctane sulfonamide [PFOSA], and perfluorodecanoic acid [PFDA]) </td> <td> Several in vitro studies in human-derived cells have shown that PFAS can modify the secretion of pro-inflammatory mediators in a dose-dependent manner [1].  PFOS exposure significantly induced IL-1 IL-4, IL-6, and IL-8 in human lymphocytes and reduced chemokines CXCL8 and CXCL10 secretion in human bronchial epithelial cells while increasing of IL-1α release [2]; both PFOS and PFOA enhanced IL-1β release in response to Poly I:C [3]; PFOS, PFOA, PFBS, PFOSA, and PFDA exposure decreased PHA-induced release of IL-4, IL-10, and IL-6 and PFOS, PFOSA, and PFDA decreased IFN-γ release in human leukocytes with PFOS as a more potent inhibitor of cytokine production than other PFAS, and leukocytes obtained from female donors appeared to be more sensitive to the in vitro immunomodulating effects of PFAS, compared to leukocytes from male donors [4]. In a rat study exposed to PFOS, increased serum levels of TNF-α and IL-6 were observed. Kupffer cells exposed to PFOS showed cell activation, which was mostly inhibited by anti-TNF-α or anti-IL-6 treatment. Moreover, NF-κB inhibitor and JNK inhibitor significantly inhibited the production of IL-6 [5,6]. </td> <td> [1] Tian et al., 2021 [2] Li et al., 2020 [3] Sørli et al., 2020 [4] Corsini et al., 2012 [5] Han et al., 2018 [6] EFSA CONTAM Panel, 2020 </td> <td> </td> </tr> <tr> <td colspan="1" rowspan="2">Sex</td> <td>Female sex (XX chromosomes)</td> <td> Females produce higher amounts of the antiviral infection cytokine IFN-α than men [1].  Estrogens are critical regulators of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as lymphocytes such as T helper 1/2 (TH1/2) cells, regulatory T-cells (Treg cells), and B cells. One of the major forms of estrogen, estradiol, has been shown to dampen the production of excessive innate inflammatory cytokines by monocytes and macrophages [2]. In the presence of progesterone, CD4+ Th cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL-4 and IL-10 [3]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct and immune response in females is enriched with activated T-cells [1]. In lactating women, higher SARS-CoV-2 reactive memory B-cells and antibody titers have been associated with the hormone prolactin [4]. Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients. </td> <td> [1] Takahashi et al., 2020 [2] Scully et al., 2020 [3] Mauvais-Jarvis et al., 2020 [4] Gonçalves et al., 2021 </td> </tr> <tr> <td>Male sex (XY chromosomes)</td> <td> Males display a higher innate immune response to SARS-CoV-2 than females, which conditions their cytokine profile. Men have higher levels of the innate immune cytokines IL-8 and IL-18 in circulation  [1]. Moreover, elderly men in particular display autoantibodies against IFN-α more frequently [5]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct. Men display higher circulating levels of non-classical monocytes [1]. Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-α [6], IL-8 and IL-18 [1], driving hyperinflammation and more pronounced lymphopenia in males. </td> <td> [5] Bastard et al., 2020 [6] Agrawal et al., 2021 </td> </tr> <tr> <td> Age </td> <td>Old people</td> <td>During aging, a subclinical chronic inflammatory response develops leading to an immune senescent state, where pathogen protective immune responses are impaired, but the production of inflammatory cytokines, such as <a href="http://bioregistry.io/genecards:IL6">IL-6</a>, is increased. This process is called inflammaging. The persistent <a href="http://bioregistry.io/genecards:IL6">IL-6</a> elevation can induce lung tissue inflammation and mortality. The rate of inflammaging is higher in men and accelerated inflammaging is believed to worsen COVID-19 outcomes [1]. The chronic inflammatory status is associated with a dramatic depletion of B lymphocyte-driven acquired immunity. Aging also attenuates the upregulation of co-stimulatory molecules critical for T-cell priming and reduces antiviral IFN production by alveolar macrophages and dendritic cells in response to infection with the influenza virus [2].</td> <td> [1] Bonafè et al., 2020 [2] Kovacs et al., 2017</td> </tr> <tr> <td rowspan="2">Lipids</td> <td> Atherogenic dyslipidemia </td> <td> Lipids impact innate and adaptive immune responses [1,2]. In COVID-19. The atherogenic dyslipidemia associated with COVID-19 severity (high tryglycerides and low total, low density lipoprotein and high density lipoprotein cholesterol) was inversely correlated with inflammatory biomarkers such as increased levels of serum C-reactive protein (CRP), <a href="http://bioregistry.io/genecards:IL6">IL-6</a>, IL-8, and IL-10 [3,4]. </td> <td rowspan="2"> [1] Hubler and Kennedy, 2016 [2] Bernardi et al., 2018 [3] Henry et al., 2021 [4] Caterino et al., 2021 [5] Hubler and Kennedy, 2016 [6] Winer et al., 2009 [7] Im et al., 2011 [8] Muscogiuri et al., 2020 </td> </tr> <tr> <td> Obesity </td> <td> In obesity, immune cells interact with various classes of lipids, which can control the plasticity of macrophages and T lymphocytes. In COVID-19. Altered lipid homeostasis is associated with severe COVID-19 outcomes and, at the same time, with chronic inflammation and inflammatory polarization of macrophages and T lymphocytes [5]. Th1 lymphocytes are more prevalent in adipose tissue of obese patients [6]. In the same way, Th1 lymphocytes are elevated in visceral fat [6]. Both macrophages and T lymphocytes interact with lipids that influence their proliferation, differentiation, polarization [7] and transcriptional regulation, which is tightly controlled by Sterol regulatory element-binding protein (SREBP) and Liver X receptors (LXRs), expressed in macrophages and known regulators of cytokine release. Adipose tissue produces many pro-inflammatory adipokines and cytokines, which lead to low-grade inflammation and the recruitment of immune cells which may clarify the connection between obesity and COVID-19 severity [8]. </td> </tr> <tr> <td>Gut microbiota</td> <td>Gut dysbiosis (alteration of gut microbiota)</td> <td> The gut microbiota is increasingly acknowledged to play a central role in human health and disease, notably by shaping the immune response. Notably some bacteria living in the gut produce short-chain fatty acids (SCFA), recognized as mediators of the intestinal inflammatory response [1]. SCFAs modulate inflammation by regulating immune cell cytokine production such as TNF-α, IL-12, IL-6 [2]. For example, butyrate decreased the lipopolysaccharide (LPS)-induced TNF-α expression in monocytes [4] and activated Treg cells, blocking an excessive inflammatory response [1,3]. In COVID-19. In a COVID-19 cohort, the depletion of several bacterial species (B. adolescentis, E. rectale and F. prausnitzii, known to play immunomodulatory roles in the human gastrointestinal system) was linked to increased plasma concentrations of TNF-α, CXCL10, CCL2 and IL-10 [4]. Conversely, two species enriched in the COVID-19 cohort, B. dorei and Akkermansia muciniphila, were positively correlated with IL-1β, IL-6 and CXCL8. Using a machine learning model [5], it was reported that the disruption of gut microbiota significantly correlated with pro-inflammatory cytokines and may predispose normal individuals to severe COVID-19. Decreases in the abundance of butyrate-producing bacteria and a decline in SCFA were observed in severe COVID-19 [4,6,7,8]. Reduced relative proportion of bacteria producing SCFA was observed in Syrian hamsters infected with SARS-CoV-2, compared to non-infected controls, with a transient decrease in systemic SCFA amounts [9]. However, SCFA supplementation in hamsters during infection had no effect on inflammatory parameters. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs in COVID-19 patients, which correlated with disease severity and increased plasma concentrations of CXCL-10 and CRP [10]. </td> <td> [1] Yoo et al., 2020 [2] Vinolo et al., 2011 [3] Atarashi et al., 2013 [4] Yeo et al., 2021 [5] Gou et al., 2021 [6] Zuo et al., 2020 [7] Gu et al., 2020 [8] Grenga et al., 2022 [9] Sencio et al., 2022 [10] Zhang et al., 2022 </td> </tr> <tr> <td>Vitamin D (low evidence)</td> <td>Vitamin D deficiency</td> <td> There is a complex interplay between vitamin D and the immune response to viral infections. Low vitamin D status is proposed to induce upregulation of the TNF-α and downstream of Nuclear Factor Kappa B Subunit 1 (NF–κB1) signaling pathway, which regulates inflammatory reactions toward viral infection in macrophages [1,2]. Vitamin D was shown as a potent suppressor of IFN-γ mediated macrophages response, preventing the release of inflammatory cytokines and chemokines [3]. Thus, release of pro-inflammatory cytokines might be exacerbated in COVID-19 patients with vitamin D deficiency [4]. </td> <td> [1] Hassan et al., 2022 [2] Książek et al., 2021 [3] Helming et al., 2005 [4] Munshi et al., 2021 </td> </tr> <tr> <td> Genetic factors </td> <td> </td> <td> The inflammatory response manifested by increased cytokine levels results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. In the 50-non-coding regions of the HO-1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T (-413) A sites, which regulate the transcriptional activity of HO-1. These polymorphisms have been shown to be associated with the occurrence and progression of numerous diseases, including COVID-19 [1]. The timing of the IFN response to SARS-CoV-2 infection can vary with viral load and genetic differences in host response. When the viral load is low, IFN responses are engaged and contribute to viral clearance, resulting in mild infection. When viral load is high and/or genetic factors slow antiviral responses, virus replication can delay the IFN response and cytokine storm can occur before adaptive responses clear the virus, resulting in severe disease including multisystem inflammatory syndrome in Children (MIS-C) [2]. </td> <td> [1] Singh et al., 2020 [2] Rowley, 2020 </td> </tr> <tr> <td colspan="1" rowspan="3"> Therapeutic intervention against COVID-19 </td> <td> Tocilizumab and Sarilumab </td> <td> Are anti-IL-6 receptor monoclonal antibodies, which reduce inflammation [1] by attaching to the IL-6 receptor (as IL-6 receptor inhibitors) [2]. Tocilizumab, a biological drug approved for rheumatoid arthritis, is currently being evaluated for its efficacy against the effects of systemic IL-6 elevation (ClinicalTrial.gov accessed on March 2022, NCT04317092, NCT04320615, NCT04306705) [3]. </td> <td> [1] WHO, 2021. [2] European Medicines Agency, 2021 [3] Bonafè et al., 2020 </td> </tr> <tr> <td> Baricitinib </td> <td> Is an immunosuppressant that blocks the action of enzymes known as Janus kinases (JK), which play an important role in inflammatory processes (JAK inhibitor) [1–4]. </td> <td> [1] Jorgensen et al., 2020 [2] Bekerman et al., 2017 [3] Neveu et al., 2015 [4] Richardson et al., 2020 </td> </tr> <tr> <td> Low molecular weight heparins (LMWHs) </td> <td> Have anti-inflammatory effects by blocking pro-inflammatory mediators (TNF-α, IL-6 and Leukotriene [LTB4]) [1]. </td> <td> [1] Buijsers et al., 2020 </td> </tr> <tr> <td colspan="1"> Pre-existing heart failure </td> <td> </td> <td> Dysregulation of renin angiotensin system due to pre-existing heart failure can have detrimental inflammatory effects both locally (in the heart) and systematically. The Angiotensin converting enzyme 2 (ACE2)/Angiotensin (Ang) (1-7) pathway is associated with the attenuation of a wide range of pro-inflammatory cytokines and chemokines, such as IL-1, IL-5, IL-6, IL-12, CCL2, TNF-α and MCP-1 [1]. </td> <td> [1] Rodrigues Prestes et al., 2017.                      </td> </tr> <tr> <td colspan="1"> Diet </td> <td> Dietary elements linked to pro-inflammatorymediators </td> <td> High-fat diets have been linked—in multiple studies—to promote an “inflammatory status” in the gut and subsequently other organs [1]. Compounds found in many plant foods may affect COVID-19 prognosis by blocking inflammatory mediators and pathways. Bousquet et al. [2,3] identified bioactive compounds contained in spices and fermented vegetables, including capsaicin, cinnamaldehyde, curcumin, genistein, gingerol, mustard oil, piperine, wasabi, and sulforaphane, that upregulate the signaling of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a potent endogenous antioxidant which blocks oxidative stress from the Angiotensin type I receptor (AT1R) axis, inhibits overproduction of proinflammatory cytokines and chemokines (including IL-6), and limits the activation of NF-κB. There is some in vitro evidence that Lactobacillus, found in many fermented foods, works through the same mechanism [4]. Finally, naringin, a compound found in citrus fruits, reduced LPS-induced IL-6 expression levels in vitro [5]. </td> <td> [1] Duan et al., 2018 [2] Bousquet et al., 2021a [3] Bousquet et al., 2020 [4] Bousquet et al., 2021b [5] Liu et al., 2022 </td> </tr> </tbody> </table>

A majority of the in vivo studies are conducted with only one dose and thus, it is difficult to derive quantitative dose-response relationships based on the existing data. However, it is clear from the studies referenced above that greater concentrations or doses of pro-fibrotic substances results in higher release of alarmins, and consequently, higher pro-inflammatory signalling. The above studies also demonstrate strong temporal relationships between the individual KEs.

Activated pro-inflammatory cells secrete pro-inflammatory mediators, and those mediators' goal is to cause signalling and response, which can lead to chronic inflammation (<a href="https://aopwiki.org/events/1497">KE1497</a>). Chronic inflammation means proinflammatory mediators increase and increased recruitment of inflammatory cells acts in a positive feedback loop, which continues a pro-inflammatory environment.

<ol> <li style="text-align:justify"> Agrawal S, Salazar J, Tran TM, Agrawal A. Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2. Front Immunol. 2021 Oct 20;12:739757. doi: 10.3389/fimmu.2021.739757.  </li> <li style="text-align:justify"> Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013 Aug 8;500(7461):232-6. doi: 10.1038/nature12331. </li> <li style="text-align:justify"> Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585. doi: 10.1126/science.abd4585. </li> <li style="text-align:justify"> Bekerman E, Neveu G, Shulla A, Brannan J, Pu SY, Wang S, Xiao F, Barouch-Bentov R, Bakken RR, Mateo R, Govero J, Nagamine CM, Diamond MS, De Jonghe S, Herdewijn P, Dye JM, Randall G, Einav S. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest. 2017 Apr 3;127(4):1338-1352. doi: 10.1172/JCI89857. </li> <li style="text-align:justify"> Bernardi S, Marcuzzi A, Piscianz E, Tommasini A, Fabris B. The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases. Int J Mol Sci. 2018 Dec 14;19(12):4058. doi: 10.3390/ijms19124058. </li> <li style="text-align:justify"> Bonafè M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020 Jun;53:33-37. doi: 10.1016/j.cytogfr.2020.04.005. </li> <li style="text-align:justify"> Bourdon JA, Saber AT, Jacobsen NR, Jensen KA, Madsen AM, Lamson JS, Wallin H, Møller P, Loft S, Yauk CL, Vogel UB. Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver. Part Fibre Toxicol. 2012 Feb 2;9:5. doi: 10.1186/1743-8977-9-5.  </li> <li style="text-align:justify"> Bousquet J, Cristol JP, Czarlewski W, Anto JM, Martineau A, Haahtela T, Fonseca SC, Iaccarino G, Blain H, Fiocchi A, Canonica GW, Fonseca JA, Vidal A, Choi HJ, Kim HJ, Le Moing V, Reynes J, Sheikh A, Akdis CA, Zuberbier T; ARIA group. Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies. Clin Transl Allergy. 2020 Dec 3;10(1):58. doi: 10.1186/s13601-020-00362-7 </li> <li style="text-align:justify"> Bousquet J, Czarlewski W, Zuberbier T, Mullol J, Blain H, Cristol JP, De La Torre R, Le Moing V, Pizarro Lozano N, Bedbrook A, Agache I, Akdis CA, Canonica GW, Cruz AA, Fiocchi A, Fonseca JA, Fonseca S, Gemicioğlu B, Haahtela T, Iaccarino G, Ivancevich JC, Jutel M, Klimek L, Kuna P, Larenas-Linnemann DE, Melén E, Okamoto Y, Papadopoulos NG, Pfaar O, Reynes J, Rolland Y, Rouadi PW, Samolinski B, Sheikh A, Toppila-Salmi S, Valiulis A, Choi HJ, Kim HJ, Anto JM. Spices to Control COVID-19 Symptoms: Yes, but Not Only…. Int Arch Allergy Immunol. 2021a;182(6):489-495. doi: 10.1159/000513538. </li> <li style="text-align:justify"> Bousquet J, Anto JM, Czarlewski W, Haahtela T, Fonseca SC, Iaccarino G, Blain H, Vidal A, Sheikh A, Akdis CA, Zuberbier T; ARIA group. Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy. 2021b Mar;76(3):735-750. doi: 10.1111/all.14549. </li> <li style="text-align:justify"> Buijsers B, Yanginlar C, Maciej-Hulme ML, de Mast Q, van der Vlag J. Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine. 2020 Sep;59:102969. doi: 10.1016/j.ebiom.2020.102969. </li> <li style="text-align:justify"> Caterino M, Gelzo M, Sol S, Fedele R, Annunziata A, Calabrese C, Fiorentino G, D'Abbraccio M, Dell'Isola C, Fusco FM, Parrella R, Fabbrocini G, Gentile I, Andolfo I, Capasso M, Costanzo M, Daniele A, Marchese E, Polito R, Russo R, Missero C, Ruoppolo M, Castaldo G. Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19. Sci Rep. 2021 Feb 3;11(1):2941. doi: 10.1038/s41598-021-82426-7. </li> <li style="text-align:justify"> Chen S, Yin R, Mutze K, Yu Y, Takenaka S, Königshoff M, Stoeger T. No involvement of alveolar macrophages in the initiation of carbon nanoparticle induced acute lung inflammation in mice. Part Fibre Toxicol. 2016 Jun 21;13(1):33. doi: 10.1186/s12989-016-0144-6.  </li> <li style="text-align:justify"> Corsini E, Sangiovanni E, Avogadro A, Galbiati V, Viviani B, Marinovich M, Galli CL, Dell'Agli M, Germolec DR. In vitro characterization of the immunotoxic potential of several perfluorinated compounds (PFCs). Toxicol Appl Pharmacol. 2012 Jan 15;258(2):248-55. doi: 10.1016/j.taap.2011.11.004. </li> <li style="text-align:justify"> Duan Y, Zeng L, Zheng C, Song B, Li F, Kong X, Xu K. Inflammatory Links Between High Fat Diets and Diseases. Front Immunol. 2018 Nov 13;9:2649. doi: 10.3389/fimmu.2018.02649 </li> <li style="text-align:justify"> EFSA Panel on Contaminants in the Food Chain (EFSA CONTAM Panel); Schrenk D, Bignami M, Bodin L, Chipman JK, Del Mazo J, Grasl-Kraupp B, Hogstrand C, Hoogenboom LR, Leblanc JC, Nebbia CS, Nielsen E, Ntzani E, Petersen A, Sand S, Vleminckx C, Wallace H, Barregård L, Ceccatelli S, Cravedi JP, Halldorsson TI, Haug LS, Johansson N, Knutsen HK, Rose M, Roudot AC, Van Loveren H, Vollmer G, Mackay K, Riolo F, Schwerdtle T. Risk to human health related to the presence of perfluoroalkyl substances in food. EFSA J. 2020 Sep 17;18(9):e06223. doi: 10.2903/j.efsa.2020.6223.  </li> <li style="text-align:justify"> European Medicines Agency. RoActemra. 2021. Available online: <a href="https://www.ema.europa.eu/en/medicines/human/EPAR/roactemra" style="color:blue; text-decoration:underline">https://www.ema.europa.eu/en/medicines/human/EPAR/roactemra</a> (accessed 12 May 2022). </li> <li style="text-align:justify"> Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007 Dec;117(12):3786-99. doi: 10.1172/JCI32285. </li> <li style="text-align:justify"> Girtsman TA, Beamer CA, Wu N, Buford M, Holian A. IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57Bl/6 mice. Nanotoxicology. 2014 Feb;8(1):17-27. doi: 10.3109/17435390.2012.744110.  </li> <li style="text-align:justify"> Glencross DA, Ho TR, Camiña N, Hawrylowicz CM, Pfeffer PE. Air pollution and its effects on the immune system. Free Radic Biol Med. 2020 May 1;151:56-68. doi: 10.1016/j.freeradbiomed.2020.01.179. </li> <li style="text-align:justify"> Gonçalves J, Juliano AM, Charepe N, Alenquer M, Athayde D, Ferreira F, Archer M, Amorim MJ, Serrano F, Soares H. Secretory IgA and T cells targeting SARS-CoV-2 spike protein are transferred to the breastmilk upon mRNA vaccination. Cell Rep Med. 2021 Dec 21;2(12):100468. doi: 10.1016/j.xcrm.2021.100468. </li> <li style="text-align:justify"> Gou W, Fu Y, Yue L, Chen GD, Cai X, Shuai M, Xu F, Yi X, Chen H, Zhu Y, Xiao ML, Jiang Z, Miao Z, Xiao C, Shen B, Wu X, Zhao H, Ling W, Wang J, Chen YM, Guo T, Zheng JS. Gut microbiota, inflammation, and molecular signatures of host response to infection. J Genet Genomics. 2021 Sep 20;48(9):792-802. doi: 10.1016/j.jgg.2021.04.002. </li> <li style="text-align:justify"> Gouwy M, De Buck M, Pörtner N, Opdenakker G, Proost P, Struyf S, Van Damme J. Serum amyloid A chemoattracts immature dendritic cells and indirectly provokes monocyte chemotaxis by induction of cooperating CC and CXC chemokines. Eur J Immunol. 2015 Jan;45(1):101-12. doi: 10.1002/eji.201444818. </li> <li style="text-align:justify"> Grenga L, Pible O, Miotello G, Culotta K, Ruat S, Roncato MA, Gas F, Bellanger L, Claret PG, Dunyach-Remy C, Laureillard D, Sotto A, Lavigne JP, Armengaud J. Taxonomical and functional changes in COVID-19 faecal microbiome could be related to SARS-CoV-2 faecal load. Environ Microbiol. 2022 Sep;24(9):4299-4316. doi: 10.1111/1462-2920.16028. </li> <li style="text-align:justify"> Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, Guo F, Zhang X, Luo R, Huang C, Lu H, Zheng B, Zhang J, Yan R, Zhang H, Jiang H, Xu Q, Guo J, Gong Y, Tang L, Li L. Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza. Clin Infect Dis. 2020 Dec 17;71(10):2669-2678. doi: 10.1093/cid/ciaa709. </li> <li style="text-align:justify"> Hadrup N, Rahmani F, Jacobsen NR, Saber AT, Jackson P, Bengtson S, Williams A, Wallin H, Halappanavar S, Vogel U. Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology. 2019 Nov;13(9):1275-1292. doi: 10.1080/17435390.2019.1654004.  </li> <li style="text-align:justify"> Halappanavar S, Nikota J, Wu D, Williams A, Yauk CL, Stampfli M. IL-1 receptor regulates microRNA-135b expression in a negative feedback mechanism during cigarette smoke-induced inflammation. J Immunol. 2013 Apr 1;190(7):3679-86. doi: 10.4049/jimmunol.1202456.  </li> <li style="text-align:justify"> Han R, Hu M, Zhong Q, Wan C, Liu L, Li F, Zhang F, Ding W. Perfluorooctane sulphonate induces oxidative hepatic damage via mitochondria-dependent and NF-κB/TNF-α-mediated pathway. Chemosphere. 2018 Jan;191:1056-1064. doi: 10.1016/j.chemosphere.2017.08.070. </li> <li style="text-align:justify"> HARRIS H. Role of chemotaxis in inflammation. Physiol Rev. 1954 Jul;34(3):529-62. doi: 10.1152/physrev.1954.34.3.529. </li> <li style="text-align:justify"> Hassan MH, Elsadek AAM, Mahmoud MA, Elsadek BEM. Vitamin D Receptor Gene Polymorphisms and Risk of Knee Osteoarthritis: Possible Correlations with TNF-α, Macrophage Migration Inhibitory Factor, and 25-Hydroxycholecalciferol Status. Biochem Genet. 2022 Apr;60(2):611-628. doi: 10.1007/s10528-021-10116-0. </li> <li style="text-align:justify"> Helming L, Böse J, Ehrchen J, Schiebe S, Frahm T, Geffers R, Probst-Kepper M, Balling R, Lengeling A. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood. 2005 Dec 15;106(13):4351-8. doi: 10.1182/blood-2005-03-1029. </li> <li style="text-align:justify"> Henry BM, Szergyuk I, de Oliveira MHS, Abosamak MF, Benoit SW, Benoit JL, Lippi G. Alterations in the lipid profile associate with a dysregulated inflammatory, prothrombotic, anti-fibrinolytic state and development of severe acute kidney injury in coronavirus disease 2019 (COVID-19): A study from Cincinnati, USA. Diabetes Metab Syndr. 2021 May-Jun;15(3):863-868. doi: 10.1016/j.dsx.2021.04.011. </li> <li style="text-align:justify"> Ho CC, Chang H, Tsai HT, Tsai MH, Yang CS, Ling YC, Lin P. Quantum dot 705, a cadmium-based nanoparticle, induces persistent inflammation and granuloma formation in the mouse lung. Nanotoxicology. 2013 Feb;7(1):105-15. doi: 10.3109/17435390.2011.635814.  </li> <li style="text-align:justify"> Hofman Z, de Maat S, Hack CE, Maas C. Bradykinin: Inflammatory Product of the Coagulation System. Clin Rev Allergy Immunol. 2016 Oct;51(2):152-61. doi: 10.1007/s12016-016-8540-0.  </li> <li style="text-align:justify"> Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells. J Nutr Biochem. 2016 Aug;34:1-7. doi: 10.1016/j.jnutbio.2015.11.002.  </li> <li style="text-align:justify"> Husain M, Kyjovska ZO, Bourdon-Lacombe J, Saber AT, Jensen KA, Jacobsen NR, Williams A, Wallin H, Halappanavar S, Vogel U, Yauk CL. Carbon black nanoparticles induce biphasic gene expression changes associated with inflammatory responses in the lungs of C57BL/6 mice following a single intratracheal instillation. Toxicol Appl Pharmacol. 2015 Dec 15;289(3):573-88. doi: 10.1016/j.taap.2015.11.003. </li> <li style="text-align:justify"> Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, Raffatellu M, Osborne TF. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 2011 May 4;13(5):540-9. doi: 10.1016/j.cmet.2011.04.001 </li> <li style="text-align:justify"> Jia H, Liu Y, Guo D, He W, Zhao L, Xia S. PM2.5-induced pulmonary inflammation via activating of the NLRP3/caspase-1 signaling pathway. Environmental Toxicology, 2021 Mar;36(3):298-307. doi: 10.1002/tox.23035.  </li> <li style="text-align:justify"> Jorgensen SCJ, Tse CLY, Burry L, Dresser LD. Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19. Pharmacotherapy. 2020 Aug;40(8):843-856. doi: 10.1002/phar.2438. </li> <li style="text-align:justify"> Kamata H, Tasaka S, Inoue K, Miyamoto K, Nakano Y, Shinoda H, Kimizuka Y, Fujiwara H, Ishii M, Hasegawa N, Takamiya R, Fujishima S, Takano H, Ishizaka A. Carbon black nanoparticles enhance bleomycin-induced lung inflammatory and fibrotic changes in mice. Exp Biol Med (Maywood). 2011 Mar;236(3):315-24. doi: 10.1258/ebm.2011.010180. </li> <li style="text-align:justify"> Khatri M, Bello D, Martin J, Bello A, Gore R, Demokritou P, et al. Chronic upper airway inflammation and systemic oxidative stress from nanoparticles in photocopier operators: Mechanistic insights. NanoImpact. 2017;5:133-45. doi: <a href="https://doi.org/10.1016/j.impact.2017.01.007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.impact.2017.01.007</a>. </li> <li style="text-align:justify"> Kido T, Tamagawa E, Bai N, Suda K, Yang HH, Li Y, Chiang G, Yatera K, Mukae H, Sin DD, Van Eeden SF. Particulate matter induces translocation of IL-6 from the lung to the systemic circulation. Am J Respir Cell Mol Biol. 2011 Feb;44(2):197-204. doi: 10.1165/rcmb.2009-0427OC.  </li> <li style="text-align:justify"> Knoll R, Schultze JL, Schulte-Schrepping J. Monocytes and Macrophages in COVID-19. Front Immunol. 2021 Jul 21;12:720109. doi: 10.3389/fimmu.2021.720109. </li> <li style="text-align:justify"> Kovacs EJ, Boe DM, Boule LA, Curtis BJ. Inflammaging and the Lung. Clin Geriatr Med. 2017 Nov;33(4):459-471. doi: 10.1016/j.cger.2017.06.002. </li> <li style="text-align:justify"> Książek A, Zagrodna A, Bohdanowicz-Pawlak A, Lwow F, Słowińska-Lisowska M. Relationships between Vitamin D and Selected Cytokines and Hemogram Parameters in Professional Football Players-Pilot Study. Int J Environ Res Public Health. 2021 Jul 2;18(13):7124. doi: 10.3390/ijerph18137124. </li> <li style="text-align:justify"> Lee S, Hwang SH, Jeong J, Han Y, Kim SH, Lee DK, Lee HS, Chung ST, Jeong J, Roh C, Huh YS, Cho WS. Nickel oxide nanoparticles can recruit eosinophils in the lungs of rats by the direct release of intracellular eotaxin. Part Fibre Toxicol. 2016 Jun 9;13(1):30. doi: 10.1186/s12989-016-0142-8.  </li> <li style="text-align:justify"> Leick M, Azcutia V, Newton G, Luscinskas FW. Leukocyte recruitment in inflammation: basic concepts and new mechanistic insights based on new models and microscopic imaging technologies. Cell Tissue Res. 2014 Mar;355(3):647-56. doi: 10.1007/s00441-014-1809-9.  </li> <li style="text-align:justify"> Li R, Guo C, Lin X, Chan TF, Lai KP, Chen J. Integrative omics analyses uncover the mechanism underlying the immunotoxicity of perfluorooctanesulfonate in human lymphocytes. Chemosphere. 2020 Oct;256:127062. doi: 10.1016/j.chemosphere.2020.127062 </li> <li style="text-align:justify"> Libby P. Fanning the flames: inflammation in cardiovascular diseases. Cardiovasc Res. 2015 Aug 1;107(3):307-9. doi: 10.1093/cvr/cvv188. </li> <li style="text-align:justify"> Liu W, Zheng W, Cheng L, Li M, Huang J, Bao S, Xu Q, Ma Z. Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Nat Prod Bioprospect. 2022 Feb 14;12(1):4. doi: 10.1007/s13659-022-00325-4. </li> <li style="text-align:justify"> Ljungman P, Bellander T, Schneider A, Breitner S, Forastiere F, Hampel R, Illig T, Jacquemin B, Katsouyanni K, von Klot S, Koenig W, Lanki T, Nyberg F, Pekkanen J, Pistelli R, Pitsavos C, Rosenqvist M, Sunyer J, Peters A. Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen polymorphisms. Environ Health Perspect. 2009 Sep;117(9):1373-9. doi: 10.1289/ehp.0800370. </li> <li style="text-align:justify"> Ma J, Li R, Qu G, Liu H, Yan B, Xia T, Liu Y, Liu S. Carbon nanotubes stimulate synovial inflammation by inducing systemic pro-inflammatory cytokines. Nanoscale. 2016 Oct 27;8(42):18070-18086. doi: 10.1039/c6nr06041b.  </li> <li style="text-align:justify"> Marchini T, Wolf D, Michel NA, Mauler M, Dufner B, Hoppe N, Beckert J, Jäckel M, Magnani N, Duerschmied D, Tasat D, Alvarez S, Reinöhl J, von Zur Muhlen C, Idzko M, Bode C, Hilgendorf I, Evelson P, Zirlik A. Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages. Basic Res Cardiol. 2016 Jul;111(4):44. doi: 10.1007/s00395-016-0562-5.  </li> <li style="text-align:justify"> Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner JG, Rubin JB, Sandberg K, Suzuki A. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020 Aug 22;396(10250):565-582. doi: 10.1016/S0140-6736(20)31561-0. </li> <li style="text-align:justify"> Morimoto Y, Ogami A, Todoroki M, Yamamoto M, Murakami M, Hirohashi M, Oyabu T, Myojo T, Nishi K, Kadoya C, Yamasaki S, Nagatomo H, Fujita K, Endoh S, Uchida K, Yamamoto K, Kobayashi N, Nakanishi J, Tanaka I. Expression of inflammation-related cytokines following intratracheal instillation of nickel oxide nanoparticles. Nanotoxicology. 2010 Jun;4(2):161-76. doi: 10.3109/17435390903518479 </li> <li style="text-align:justify"> Munshi R, Hussein MH, Toraih EA, Elshazli RM, Jardak C, Sultana N, Youssef MR, Omar M, Attia AS, Fawzy MS, Killackey M, Kandil E, Duchesne J. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. J Med Virol. 2021 Feb;93(2):733-740. doi: 10.1002/jmv.26360. </li> <li style="text-align:justify"> Muscogiuri G, Pugliese G, Barrea L, Savastano S, Colao A. Commentary: Obesity: The "Achilles heel" for COVID-19? Metabolism. 2020 Jul;108:154251. doi: 10.1016/j.metabol.2020.154251. </li> <li style="text-align:justify"> Neveu G, Ziv-Av A, Barouch-Bentov R, Berkerman E, Mulholland J, Einav S. AP-2-associated protein kinase 1 and cyclin G-associated kinase regulate hepatitis C virus entry and are potential drug targets. J Virol. 2015 Apr;89(8):4387-404. doi: 10.1128/JVI.02705-14. </li> <li style="text-align:justify"> Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0.  </li> <li style="text-align:justify"> Patowary P, Pathak MP, Zaman K, Dwivedi SK, Chattopadhyay P. Innate inflammatory response to acute inhalation exposure of riot control agent oleoresin capsicum in female rats: An interplay between neutrophil mobilization and inflammatory markers. Exp Lung Res. 2020 Apr-May;46(3-4):81-97. doi: 10.1080/01902148.2020.1733709.  </li> <li style="text-align:justify"> Petri B, Sanz MJ. Neutrophil chemotaxis. Cell Tissue Res. 2018 Mar;371(3):425-436. doi: 10.1007/s00441-017-2776-8.  </li> <li style="text-align:justify"> Porter DW, Ye J, Ma J, Barger M, Robinson VA, Ramsey D, McLaurin J, Khan A, Landsittel D, Teass A, Castranova V. Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage. Inhal Toxicol. 2002 Apr;14(4):349-67. doi: 10.1080/08958370252870998.  </li> <li style="text-align:justify"> Porter DW, Orandle M, Zheng P, Wu N, Hamilton RF Jr, Holian A, Chen BT, Andrew M, Wolfarth MG, Battelli L, Tsuruoka S, Terrones M, Castranova V. Mouse pulmonary dose- and time course-responses induced by exposure to nitrogen-doped multi-walled carbon nanotubes. Inhal Toxicol. 2020 Jan;32(1):24-38. doi: 10.1080/08958378.2020.1723746. </li> <li style="text-align:justify"> Poulsen SS, Jacobsen NR, Labib S, Wu D, Husain M, Williams A, Bøgelund JP, Andersen O, Købler C, Mølhave K, Kyjovska ZO, Saber AT, Wallin H, Yauk CL, Vogel U, Halappanavar S. Transcriptomic analysis reveals novel mechanistic insight into murine biological responses to multi-walled carbon nanotubes in lungs and cultured lung epithelial cells. PLoS One. 2013 Nov 19;8(11):e80452. doi: 10.1371/journal.pone.0080452. </li> <li style="text-align:justify"> Rahman L, Wu D, Johnston M, William A, Halappanavar S. Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. Mutagenesis. 2017 Jan;32(1):59-76. doi: 10.1093/mutage/gew048.  </li> <li style="text-align:justify"> Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, Rawling M, Savory E, Stebbing J. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31. doi: 10.1016/S0140-6736(20)30304-4. </li> <li style="text-align:justify"> Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes-E-Silva AC. The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research. Curr Drug Targets. 2017;18(11):1301-1313. doi: 10.2174/1389450117666160727142401 </li> <li style="text-align:justify"> Rowley AH. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol. 2020 Aug;20(8):453-454. doi: 10.1038/s41577-020-0367-5. </li> <li style="text-align:justify"> Schremmer I, Brik A, Weber DG, Rosenkranz N, Rostek A, Loza K, Brüning T, Johnen G, Epple M, Bünger J, Westphal GA. Kinetics of chemotaxis, cytokine, and chemokine release of NR8383 macrophages after exposure to inflammatory and inert granular insoluble particles. Toxicol Lett. 2016 Nov 30;263:68-75. doi: 10.1016/j.toxlet.2016.08.014. </li> <li style="text-align:justify"> Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol. 2020 Jul;20(7):442-447. doi: 10.1038/s41577-020-0348-8. </li> <li style="text-align:justify"> Sencio V, Machelart A, Robil C, Benech N, Hoffmann E, Galbert C, Deryuter L, Heumel S, Hantute-Ghesquier A, Flourens A, Brodin P, Infanti F, Richard V, Dubuisson J, Grangette C, Sulpice T, Wolowczuk I, Pinet F, Prévot V, Belouzard S, Briand F, Duterque-Coquillaud M, Sokol H, Trottein F. Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters. Gut Microbes. 2022 Jan-Dec;14(1):2018900. doi: 10.1080/19490976.2021.2018900. </li> <li style="text-align:justify"> Signorini C, Pignatti P, Coccini T. How Do Inflammatory Mediators, Immune Response and Air Pollution Contribute to COVID-19 Disease Severity? A Lesson to Learn. Life (Basel). 2021 Feb 25;11(3):182. doi: 10.3390/life11030182. </li> <li style="text-align:justify"> Singh D, Wasan H, Reeta KH. Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications. Free Radic Biol Med. 2020 Dec;161:263-271. doi: 10.1016/j.freeradbiomed.2020.10.016. </li> <li style="text-align:justify"> Song JA, Park HJ, Yang MJ, Jung KJ, Yang HS, Song CW, Lee K. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxicol. 2014 Jul;69:267-75. doi: 10.1016/j.fct.2014.04.027.  </li> <li style="text-align:justify"> Sørli JB, Låg M, Ekeren L, Perez-Gil J, Haug LS, Da Silva E, Matrod MN, Gützkow KB, Lindeman B. Per- and polyfluoroalkyl substances (PFASs) modify lung surfactant function and pro-inflammatory responses in human bronchial epithelial cells. Toxicol In Vitro. 2020 Feb;62:104656. doi: 10.1016/j.tiv.2019.104656. </li> <li style="text-align:justify"> Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, Silva J, Mao T, Oh JE, Tokuyama M, Lu P, Venkataraman A, Park A, Liu F, Meir A, Sun J, Wang EY, Casanovas-Massana A, Wyllie AL, Vogels CBF, Earnest R, Lapidus S, Ott IM, Moore AJ; Yale IMPACT Research Team; Shaw A, Fournier JB, Odio CD, Farhadian S, Dela Cruz C, Grubaugh ND, Schulz WL, Ring AM, Ko AI, Omer SB, Iwasaki A. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020 Dec;588(7837):315-320. doi: 10.1038/s41586-020-2700-3. </li> <li style="text-align:justify"> Tian J, Hong Y, Li Z, Yang Z, Lei B, Liu J, Cai Z. Immunometabolism-modulation and immunotoxicity evaluation of perfluorooctanoic acid in macrophage. Ecotoxicol Environ Saf. 2021 Jun 1;215:112128. doi: 10.1016/j.ecoenv.2021.112128. </li> <li style="text-align:justify"> Tsai DH, Amyai N, Marques-Vidal P, Wang JL, Riediker M, Mooser V, Paccaud F, Waeber G, Vollenweider P, Bochud M. Effects of particulate matter on inflammatory markers in the general adult population. Particle and Fibre Toxicolgy. 2012 Jul 6;9:24. doi: 10.1186/1743-8977-9-24 </li> <li> Villeneuve DL, Landesmann B, Allavena P, Ashley N, Bal-Price A, Corsini E, Halappanavar S, Hussell T, Laskin D, Lawrence T, Nikolic-Paterson D, Pallardy M, Paini A, Pieters R, Roth R, Tschudi-Monnet F. Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways. Toxicol Sci. 2018 Jun 1;163(2):346-352. doi: 10.1093/toxsci/kfy047.  </li> <li> Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011 Oct;3(10):858-76. doi: 10.3390/nu3100858. </li> <li style="text-align:justify"> Wang G, Zhang X, Liu X, Zheng J, Chen R, Kan H. Ambient fine particulate matter induce toxicity in lung epithelial-endothelial co-culture models. Toxicol Lett. 2019 Feb;301:133-145. doi: 10.1016/j.toxlet.2018.11.010.  </li> <li style="text-align:justify"> Westphal GA, Schremmer I, Rostek A, Loza K, Rosenkranz N, Brüning T, Epple M, Bünger J. Particle-induced cell migration assay (PICMA): A new in vitro assay for inflammatory particle effects based on permanent cell lines. Toxicol In Vitro. 2015 Aug;29(5):997-1005. doi: 10.1016/j.tiv.2015.04.005.  </li> <li style="text-align:justify"> World Health Organization, 2021. Therapeutics and COVID-19: Living Guideline. WHO/2019-NCoV/Therapeutics/2021.1'. IL-6 Receptor Blockers 2021. Available online: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.4 (accessed 12 May 2022). </li> <li style="text-align:justify"> Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009 Aug;15(8):921-9. doi: 10.1038/nm.2001 </li> <li style="text-align:justify"> Yamasaki K, Eeden SFV. Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD. Int J Mol Sci. 2018 Feb 15;19(2):582. doi: 10.3390/ijms19020582. </li> <li style="text-align:justify"> Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS, Chow KM, Ng SSS, Li TC, Ng RW, Yip TC, Wong GL, Chan FK, Wong CK, Chan PK, Ng SC. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021 Apr;70(4):698-706. doi: 10.1136/gutjnl-2020-323020. </li> <li style="text-align:justify"> Yoo JY, Groer M, Dutra SVO, Sarkar A, McSkimming DI. Gut Microbiota and Immune System Interactions. Microorganisms. 2020 Oct 15;8(10):1587. doi: 10.3390/microorganisms8101587. </li> <li style="text-align:justify"> Zhang F, Wan Y, Zuo T, Yeoh YK, Liu Q, Zhang L, Zhan H, Lu W, Xu W, Lui GCY, Li AYL, Cheung CP, Wong CK, Chan PKS, Chan FKL, Ng SC. Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19. Gastroenterology. 2022 Feb;162(2):548-561.e4. doi: 10.1053/j.gastro.2021.10.013. </li> <li style="text-align:justify"> Zhao J, Gao Z, Tian Z, Xie Y, Xin F, Jiang R, Kan H, Song W. The biological effects of individual-level PM(2.5) exposure on systemic immunity and inflammatory response in traffic policemen. Occup Environ Med. 2013 Jun;70(6):426-31. doi: 10.1136/oemed-2012-100864. </li> <li style="text-align:justify"> Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, Wan Y, Chung ACK, Cheung CP, Chen N, Lai CKC, Chen Z, Tso EYK, Fung KSC, Chan V, Ling L, Joynt G, Hui DSC, Chan FKL, Chan PKS, Ng SC. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 2020 Sep;159(3):944-955.e8. doi: 10.1053/j.gastro.2020.05.048. </li> </ol>   AOPWiki 2018-01-05T13:18:46

2023-05-18T12:46:20

<upstream-id>aa9150f8-c4c1-436c-971d-ccfa9ec530fc</upstream-id> <downstream-id>fd9768b0-9049-40ac-bed8-7b04b1d09013</downstream-id>

AOPWiki 2022-05-25T05:47:05

2022-05-25T05:47:05

<upstream-id>446e191c-ec98-47d1-abc6-84ee49609a6c</upstream-id> <downstream-id>a4dcf5ca-cc3e-4309-b530-1faa8a9091ba</downstream-id>

AOPWiki 2022-05-25T05:32:06

2022-05-25T05:32:06

<upstream-id>a4dcf5ca-cc3e-4309-b530-1faa8a9091ba</upstream-id> <downstream-id>a6f1bf33-11a3-4c70-977e-1ea30d3d4990</downstream-id>

AOPWiki 2022-05-25T05:51:53

2022-05-25T05:51:53

<upstream-id>a4dcf5ca-cc3e-4309-b530-1faa8a9091ba</upstream-id> <downstream-id>85c86a3d-fe90-4d1c-9a6b-df8deace1bb5</downstream-id>

AOPWiki 2022-05-25T05:35:02

2022-05-25T05:35:02

<upstream-id>85c86a3d-fe90-4d1c-9a6b-df8deace1bb5</upstream-id> <downstream-id>a6f1bf33-11a3-4c70-977e-1ea30d3d4990</downstream-id>

AOPWiki 2022-05-25T05:35:27

2022-05-25T05:35:27

<upstream-id>a6f1bf33-11a3-4c70-977e-1ea30d3d4990</upstream-id> <downstream-id>fd9768b0-9049-40ac-bed8-7b04b1d09013</downstream-id>

AOPWiki 2022-05-25T05:35:49

2022-05-25T05:35:49

<upstream-id>fd9768b0-9049-40ac-bed8-7b04b1d09013</upstream-id> <downstream-id>2537bd3d-4803-448d-84ed-a472d739f8f7</downstream-id>

AOPWiki 2019-07-03T11:53:38

2019-07-03T11:53:38

<upstream-id>2537bd3d-4803-448d-84ed-a472d739f8f7</upstream-id> <downstream-id>5e1ae781-8f61-42a1-8809-ddebdc28d13a</downstream-id>

AOPWiki 2019-07-03T11:53:50

2019-07-03T11:53:50

Interaction with lung resident cell membrane components leads to lung cancer

Interaction with lung cells leads to lung cancer

Penny Nymark

Penny Nymark1 Hanna L. Karlsson1 Sabina Halappanavar2 Ulla Vogel3,4 1 Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden 2 Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada 3 National Research Centre for the Working Environment, Copenhagen, Denmark 4 DTU Health Tech, Technical University of Denmark, Kgs. Lyngby, Denmark Funding: <a href="https://forskautandjurforsok.se/">Swedish Fund for Research without Animals</a> (grants N0005-2020 and F0005-2021)

BY-SA

2.0

This AOP was developed and first presented in <a href="https://doi.org/10.3389/ftox.2021.653386">Nymark et al. 2021</a>. The particulate fraction of diesel exhaust is known to be required for carcinogenesis, since filtered exhaust does not cause lung cancer in rodents (Brightwell et al., 1989). Inhaled, nanosized particles deposit primarily in the alveolar region, where clearance is low, and lead to prolonged particle retention enabling particle-bio interaction (Oberdörster et al., 2005; Gaté et al., 2017). Interaction between particles and lung resident cell membrane components (Figure 1A below in the Background section, MIE) leads to inflammation (KE1A) which is proportional to the total deposited surface area (Schmid and Stoeger, 2016; Danielsen et al., 2020; Kokot et al., 2020). The persistence of particles results in long-lasting inflammation (Hougaard et al., 2010; Chézeau et al., 2018). Metabolic activity of pro-inflammatory cells induces formation of ROS, which may also be augmented by the surface reactivity of particles themselves (Jacobsen et al., 2008b; Bendtsen et al., 2020). The sustained inflammatory signaling and concomitant synthesis of reactive radicals, cause a chronic state of oxidant-antioxidant imbalance and loss of protective mechanisms, potentially resulting in secondary genotoxicity (KE1B) (Evans et al., 2019a). Diesel exhaust consists of nanosized particles of inorganic and organic carbon with associated metal oxides and polyaromatic hydrocarbons (PAHs) (Taxell and Santonen, 2016; Bendtsen et al., 2020). Both the carbon core and solvent-extractable fractions containing PAHs are mutagenic in vivo and several metal (oxides) have been classified as (possibly) carcinogenic (IARC, 2006, 2012b; Hashimoto et al., 2007). It is possible that such genotoxic agents leach from the pulmonary deposited particles leading to activation of alternative AOPs associated with the formation of bulky DNA adducts and resulting in accumulation of mutations (Li and Nel, 2006) as indicated by the alternative path in Figure 1A below in the Background section (in gray) (Sasaki et al., 2020). In addition, the insoluble carbon core generates particle-induced ROS leading to oxidative stress (KE1C) (Bendtsen et al., 2020; Gren et al., 2020). In a recent study of five diesel exhaust particles designed to differ in chemical composition, DNA strand breaks (KE2) in bronchoalveolar lavage cells were found to correlate with the ROS forming capacity of the particles (Bendtsen et al., 2020). Similarly, carbon black generates surface-dependent ROS, causing oxidative DNA damage (KE2) and mutagenicity (KE3) in vivo and in vitro (Jacobsen et al., 2008b). Finally, direct interactions between nanosized particles and DNA or the mitotic spindle are also possible, and the AOP features a direct link between the MIE and mutagenicity, i.e., KE3 (Buliaková et al., 2017; Patel et al., 2017). Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity (Figure 1). The AOP provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.   <img alt="Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles" src="https://www.frontiersin.org/files/Articles/653386/ftox-03-653386-HTML-r1/image_m/ftox-03-653386-g001.jpg" style="height:609px; width:1084px" /> Figure 1. A putative AOP for pulmonary deposition and retention of nanosized foreign matter leading to lung cancer, including anchored in silico and in vitro methods. (A) A putative AOP developed based on information and knowledge about the process-generated and engineered nanoparticles diesel exhaust, carbon black, and TiO2. Suggested relevant existing KEs in the AOP-Wiki, that could serve for informing development of the proposed AOP, are mentioned within parentheses. (B) The AOP supports integrated application of in silico- and in vitro-based standard OECD tests with new approach methodologies (NAMs), including models/approaches for prediction of deposited dose, detection of ROS generation, inflammation, DNA damage, mutations, and cell transformation. Examples of specific assays are provided at the bottom. MIE, molecular initiating event; KE, key event; AO, adverse outcome; AOP, adverse outcome pathway; IC-PMS, inductively coupled plasma mass spectrometry; AAS, atomic absorption spectroscopy; TEM, transmission electron microscopy; ROS, reactive oxygen species; DCFH-DA, 2'-7'dichlorofluorescin diacetate; GSH, glutathione; ELISA, enzyme-linked immunosorbent assay; HT, high-throughput; FPG, formamidopyrimidine DNA glycosylase; OECD, Organization for Economic Co-operation and Development; HPRT, hypoxanthine phosphorybosyl transferase; TK, thymidine kinase; FE1-MML, FE1-MutaMouse lung epithelial cells.

As stated earlier, there are many different ways by which pro-fibrotic stressors can interact with the components of cell membrane and often involve multiple interactions at the same time. Few studies investigate the exact interaction between the stressor and the cellular membrane components. Asbestos and silica crystals engage scavenger receptors present on the macrophages (Murthy et al., 2015). Bleomycin binds high affinity bleomycin binding sites present on rat alveolar macrophage surfaces, leading to macrophage activation (Denholm and Phan, 1990). However, the consequences of such interactions such as, the release of PRR agonists DAMPs (alarmins) from dying or injured cells, increased  gene or protein synthesis downstream of receptor binding or in the case of NMs, their cellular uptake, are measured routinely as indicative of occurrence of such interactions (Nel et al., 2009; Cheng et al., 2013). Because of the phys-chem properties such as surface charge, NMs and asbestos like materials can bind to cellular macromolecules and cell surface/membrane components, which in turn, facilitate their uptake and intracellular sequestration by the cells (NIOSH, 2011a; Pascolo et al., 2013). Several DAMPs that can be effectively measured in biological samples and cultured cells include High Mobility Group Binding 1 (HMGB1) protein, Heat Shock proteins (HSPs), uric acid, annexins, and S100 proteins (Bianchi, 2007). Of all DAMPs, interleukin (IL)-1α is the most commonly measured alarmin. IL-1α is the principal pro-inflammatory moiety and is a designated ‘alarmin’ in the cell that alerts the host to injury or damage (Di Paolo and Shayakhmetov, 2016). It is shown that administration of necrotic cells to mice results in neutrophilic inflammation that was entirely mediated by IL-1α released from the dying or necrosed cells and consequent activation of IL-1 Receptor 1 (IL-1R1) signalling (<a href="#auth-1">Suwar</a><a href="#a1">a</a> et al., 2014). IL-1α is released following exposure to MWCNTs (Nikota et al., 2017) and silica (Rabolli et al., 2014). Although IL1-b is not a designated alarmin, its secretion following exposure to stressors is routinely assessed and is linked to initiation of cell or tissue injury. Other high aspect ratio fibres such as asbestos and CNTs induce frustrated phagocytosis and acute cell injury (Boyles et al., 2015; Dörger et al., 2001; Brown et al., 2007; Kim et al., 2010; Poland et al., 2008), leading to DAMP release (Nikota et al, 2017), inflammation and immune responses.

adjacent

Moderate

Moderate adjacent

Low

Moderate adjacent

Moderate

Moderate adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Low

High non-adjacent

Not Specified

Not Specified non-adjacent

Not Specified

Not Specified non-adjacent

Not Specified

High

Not Specified

Nymark P, Karlsson HL, Halappanavar S, Vogel U. <a href="https://pubmed.ncbi.nlm.nih.gov/35295099/">Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles.</a> Front Toxicol. 2021 Apr 29;3:653386. <a href="https://doi.org/10.3389/ftox.2021.653386">https://doi.org/10.3389/ftox.2021.653386</a>. eCollection 2021. Bendtsen, K. M., Gren, L., Malmborg, V. B., Shukla, P. C., Tunér, M., Essig, Y. J., et al. (2020). Particle characterization and toxicity in C57BL/6 mice following instillation of five different diesel exhaust particles designed to differ in physicochemical properties. Part Fibre Toxicol. 17:38. doi: 10.1186/s12989-020-00369-9 Brightwell, J., Fouiliet, X., Cassano-Zoppi, A.-L., Bernstein, D., Crawley, F., Duchosal, F., et al. (1989). Tumours of the respiratory tract in rats and hamsters following chronic inhalation of engine exhaust emissions. J. Appl. Toxicol. 9, 23–31. doi: 10.1002/jat.2550090106 Buliaková, B., Mesáro&scaron;ová, M., Bábelová, A., &Scaron;elc, M., Némethová, V., &Scaron;ebová, L., et al. (2017). Surface-modified magnetite nanoparticles act as aneugen-like spindle poison. Nanomedicine 13, 69–80. doi: 10.1016/j.nano.2016.08.027 Chézeau, L., Sébillaud, S., Safar, R., Seidel, C., Dembélé, D., Lorcin, M., et al. (2018). Short- and long-term gene expression profiles induced by inhaled TiO2 nanostructured aerosol in rat lung. Toxicol. Appl. Pharmacol. 356, 54–64. doi: 10.1016/j.taap.2018.07.013 Danielsen, P. H., Knudsen, K. B., &Scaron;trancar, J., Umek, P., Koklič, T., Garvas, M., et al. (2020). Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice. Toxicol. Appl. Pharmacol. 386:114830. doi: 10.1016/j.taap.2019.114830 Evans, S. J., Clift, M. J. D., Singh, N., Wills, J. W., Hondow, N., Wilkinson, T. S., et al. (2019a). In vitro detection of in vitro secondary mechanisms of genotoxicity induced by engineered nanomaterials. Part. Fibre Toxicol. 16:8. doi: 10.1186/s12989-019-0291-7 Gaté, L., Disdier, C., Cosnier, F., Gagnaire, F., Devoy, J., Saba, W., et al. (2017). Biopersistence and translocation to extrapulmonary organs of titanium dioxide nanoparticles after subacute inhalation exposure to aerosol in adult and elderly rats. Toxicol. Lett. 265, 61–69. doi: 10.1016/j.toxlet.2016.11.009 Gren, L., Malmborg, V. B., Jacobsen, N. R., Shukla, P. C., Bendtsen, K. M., Eriksson, A. C., et al. (2020). Effect of renewable fuels and intake O2 concentration on diesel engine emission characteristics and Reactive Oxygen Species (ROS) formation. Atmosphere 11:641. <a href="https://www.mdpi.com/2073-4433/11/6/641/htm%2010.3390/atmos11060641" style="box-sizing:border-box; outline:none; word-break:break-word; font-variant-ligatures:normal; text-align:start; color:blue; text-decoration:underline">https://www.mdpi.com/2073-4433/11/6/641/htm 10.3390/atmos11060641</a> Hashimoto, A. H., Amanuma, K., Hiyoshi, K., Sugawara, Y., Goto, S., Yanagisawa, R., et al. (2007). Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust. Environ. Mol. Mutagen 48, 682–693. doi: 10.1002/em.20335 Hougaard, K. S., Jackson, P., Jensen, K. A., Sloth, J. J., Löschner, K., Larsen, E. H., et al. (2010). Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre Toxicol. 7:16. doi: 10.1186/1743-8977-7-16 IARC (2006). Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphideand Vanadium Pentoxide. Monograph 86. Available online at: <a href="https://monographs.iarc.fr/wp-content/uploads/2018/06/mono86.pdf" style="box-sizing:border-box; outline:none; word-break:break-word; font-variant-ligatures:normal; text-align:start; color:blue; text-decoration:underline">https://monographs.iarc.fr/wp-content/uploads/2018/06/mono86.pdf</a> IARC (2010). Carbon Black, Titanium Dioxide, and Talc.Monograph 93. Available online at: https://publications.iarc.fr/111 IARC (2012a). Diesel and Gasoline Engine Exhausts and Some Nitroarenes. Monograph 105. Available online at: https://publications.iarc.fr/129 IARC (2012b). Review of Human Carcinogens (Package of 6 Volumes: A,B,C,D,E,F). Monograph 100. Available online at:: https://monographs.iarc.fr/wp-content/ uploads/2018/06/mono100C-10.pdf IARC (2014). Some Nanomaterials and Some Fibres. Monograph 111. Available online at:: https://publications.iarc.fr/552 Jacobsen, N. R., Pojana, G., White, P., Møller, P., Cohn, C. A., Smith Korsholm, K., et al. (2008b). Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-Muta™Mouse lung epithelial cells. Environ. Mol. Mutagen 49, 476–487. doi: 10.1002/em.20406 Kokot, H., Kokot, B., Sebastijanović, A., Voss, C., Podlipec, R., Zawilska, P., et al. (2020). Prediction of chronic inflammation for inhaled particles: the impact of material cycling and quarantining in the lung epithelium. Adv. Mater. 32:2003913. doi: 10.1002/adma.202003913 Li, N., and Nel, A. E. (2006). The cellular impacts of diesel exhaust particles: beyond inflammation and death. Eur. Respir. J. 27, 667–668. doi: 10.1183/09031936.06.00025006 Oberdörster, G., Oberdörster, E., and Oberdörster, J. (2005). Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ. Health Perspect. 113, 823–839. doi: 10.1289/ehp.7339 Patel, S., Patel, P., and Bakshi, S. R. (2017). Titanium dioxide nanoparticles: an in vitro study of DNA binding, chromosome aberration assay, and comet assay. Cytotechnology 69, 245–263. doi: 10.1007/s10616-016-0054-3 Sasaki, J. C., Allemang, A., Bryce, S. M., Custer, L., Dearfield, K. L., Dietz, Y., et al. (2020). Application of the adverse outcome pathway framework to genotoxic modes of action. Environ. Mol. Mutagen. 61, 114–134. doi: 10.1002/em.22339 Schmid, O., and Stoeger, T. (2016). Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung. J. Aerosol. Sci. 99, 133–143. doi: 10.1016/j.jaerosci.2015.12.006 Taxell, P., and Santonen, T. (2016). Diesel Engine Exhaust. Occupational and Environmental Medicine. The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals and the Dutch Expert Committee on Occupational Safety. Available online at: <a href="https://gupea.ub.gu.se/bitstream/2077/44340/1/gupea_2077_44340_1.pdf" style="box-sizing:border-box; outline:none; word-break:break-word; font-variant-ligatures:normal; text-align:start; color:blue; text-decoration:underline">https://gupea.ub.gu.se/bitstream/2077/44340/1/gupea_2077_44340_1.pdf</a>                   AOPWiki 2022-05-25T05:09:25

2023-04-29T16:03:06