TRPA1 activation, TRPA1 Receptor

11056-06-7

Bleomycin

Bleo Bleocin Blenamax Bleo-Kyowa Bleomycins NSC 125066

DTXSID1030862

PR:000001065

PR transient receptor potential cation channel TRPV1

FMA:66768

FMA Epithelial cell

GO:0023052

GO signaling

GO:0006954

GO inflammatory response

GO:0001837

GO epithelial to mesenchymal transition

WIKI increased

WIKI occurrence

Bleomycin Bleomycin is a potent anti-tumour drug, routinely used for treating various types of human cancers (Umezawa et al., 1967; Adamson, 1976). Lung injury and lung fibrosis are the major adverse effects of this drug in humans (Hay J et al., 1991). Bleomycin is shown to induce lung fibrosis in experimental animals - in dogs (Fleischman et al., 1971), mice (Adamson IY and Bowden DH, 1974), hamsters (Snider GL et al., 1978) and is widely used as a model chemical to study the mechanisms of fibrosis in humans (reviewed in Moeller et al., 2008; Gilhodes et al., 2017). <ol> <li>Adamson, I. (1976). Pulmonary Toxicity of Bleomycin. Environmental Health Perspectives, 16, p.119.</li> <li>Adamson, IYR. and Bowden, DH. (1974). The Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis in Mice. The American Journal of Pathology. 77(2), pp185-198.</li> <li>Fleischman, R., Baker, J., Thompson, G., Schaeppi, U., Illievski, V., Cooney, D. and Davis, R. (1971). Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26(6), pp.675-682.</li> <li>Gilhodes, J., Julé, Y., Kreuz, S., Stierstorfer, B., Stiller, D. and Wollin, L. (2017). Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis. PLOS ONE, 12(1), p.e0170561.</li> <li>Hay, J., Shahzeidi, S. and Laurent, G. (1991). Mechanisms of bleomycin-induced lung damage. Archives of Toxicology, 65(2), pp.81-94.</li> <li>Moeller, A., Ask, K., Warburton, D., Gauldie, J. and Kolb, M. (2008). The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. The International Journal of Biochemistry & Cell Biology, 40(3), pp.362-382.</li> <li>Snider GL., Celli, BR., Goldstein, RH., O'Brien, JJ. and Lucey, EC. (1978). Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. Am Rev Respir Dis. Feb; 117(2). pp289-97.</li> <li>Umezawa, H., Ishizuka, M., Maeda, K. and Takeuchi, T. (1967). Studies on bleomycin. Cancer, 20(5), pp.891-895.</li> </ol>

2018-01-01T16:45:53

2019-10-29T13:08:19

Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres   Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera, Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera, Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison

2018-01-01T17:51:04

2018-01-01T17:52:30

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

WCS_9606

common toxicological species humans

10090

NCBI mouse

10116

NCBI rat

WCS_9606

common toxicological species human

TRPA1 activation, TRPA1 Receptor

Molecular

CL:0000540

CL neuron

AOPWiki 2016-11-29T18:41:30

2017-09-16T10:17:33

Increase, Inflammation

Cellular

Inflammation is complex to define.  Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes.  In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).  For review of inflammation caused by microplastics in mammals, see Wright and Kelly (2017).     Inflammation can be defined as the response of the organism to a tissue injury (Coussens). Indeed, in order to heal this injury, a multitude of chemical signals initiate and maintain a host response. Leukocytes (neutrophils, monocytes and eosinophils) are recruited to the site of the damage through the attraction by chemokines (TNF-α (tumour necrosis factor-α), interleukines…). A provisional extracellular matrix (ECM) is created, and fibroblast and endothelial cells proliferate and migrate to it. Wound healing is an example of physiological inflammation and is self-limiting (Coussens). In case of a dysregulation, inflammation can lead to pathologies. Inflammation can be caused by physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma (Singh). Inflammation was described as one of the hallmarks of cancer by Hannahan et al. as a response to tumor invasion through mainly two mechanisms: promoting genetic instatbility and supply pro-tumorogenic factors. First, inflammation in cancer promotes genetic instability (Mantovani, colotta). Macrophages, in contact with the inflammatory site can be responsible of a reactive stress oxygen reaction (ROS) (Maeda, Pollard, Grivennikov). Indeed, they generate high levels of reactive oxygen and nitrogen species which produce mutagenic agents (peroxynitrite), which in turn causes DNA mutations. Second, in inflammation, the tumor micro environment plays a critical role (Coussens). Indeed, in can supply growth factors, survival factors, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT and other hallmark-facilitating programs (Hannahan). For example, macrophages can become tumor associated macrophage which promote cell proliferation, angiogenesis, and invasion (Singh, Lin, Qian). Moreover, chronic inflammation can also lead to tumorigenesis (Karin, Singh). Indeed, since 1863, Virchow has hypothesized that chronic inflammation causes cell proliferation (Balkwill). According to Aggarwall, several pro-inflammatory markers such as TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX mediate suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis (Aggarwal).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).   Several assays can be used to measure inflammation: <ul> <li style="text-align:justify">Histopathology on samples. Several scoring tools exist (Goeboes)</li> <li style="text-align:justify">Measuring chemokines in the blood (ELISA, multiplex bead assays : interleukines (IL1, IL6), TNF, interferon… ) (Brenner) and histopathology samples</li> <li style="text-align:justify">Measuring Prostaglandin levels, COX-2 (ELISA Liquid chromatography/tandem mass spectrometry, IHC)</li> <li style="text-align:justify">Transcription factors : STAT3 Activation, NF-κB Activation (ELISA RtPCR to measure mRNA</li> <li style="text-align:justify">Biomarkers (white cell count, CRP) ratios, and predictive score using </li> <li style="text-align:justify">Measuring ROS(DCFDA, horseradish peroxidase (HRP)-oxidizing substrates, SOD-inhibitable reduction of cytochrome c) (Murphy).</li> </ul>   Methods are extensively reviewed in Marchand et al and Murphy et al.

Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).   Extensive data exists on the presence of inflammation in human (Coussens, Aggarwal, Hannhan, Mantovani..) In human, many examples of chronic inflammation leading to cancer or cancer progression exist. For instance, Helicobacter pylori infection leads to gut cancer (Wang).

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High High High

Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013">https://doi.org/10.1016/j.tox.2016.10.013</a> Palmer, S.M., Flake, G.P., Kelly, F.L., Zhang, H.L., Nugent, J.L., Kirby, P.J., Zhang, H.L., Nugent, J.L., Kirby, P.J., Foley, J.F., Gwinn, W.M., and Morgan, D.L. 2011. Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). <a href="https://doi.org/10.1371/journal.pone.0017644">https://doi.org/10.1371/journal.pone.0017644</a>   Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014 Apr 10;345(2):196-202. doi: 10.1016/j.canlet.2013.08.016. Epub 2013 Aug 24. PMID: 23981572. Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression. J Clin Invest. 1993;91:2194–206. Coussens L.M. and Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035. Wright, S.L. and Kelly, F.J.  2017.  Plastic and human health: a micro issue?  Enviromental Science and Technology 51: 6634-6647. Villeneuve, D.L., Landesmann, B., Allavena, P., Ashley, N., Bal-Price, A., Corsini, E., Halappanavar, S., Hussell, T., Laskin, D., Lawrence, T., Nikolic-Paterson, D., Pallary, M., Paini, A., Pietrs, R., Roth, R., and Tschudi-Monnet, F.  2018.  Toxicological Sciences 163(2): 346-352.     Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010 Apr 2;141(1):39-51. doi: 10.1016/j.cell.2010.03.014. PMID: 20371344; PMCID: PMC4994190. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: How hot is the link? Biochem Pharmacol. 2006;72:1605–21 Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019 Jul-Sep;18(3):121-126. doi: 10.4103/aam.aam_56_18. PMID: 31417011; PMCID: PMC6704802. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545 Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44 Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability.  Maeda H, Akaike T. Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 1998;63:854–65. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8 Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12, 76 (2019). <a href="https://doi.org/10.1186/s13045-019-0760-3" style="color:#467886; text-decoration:underline">https://doi.org/10.1186/s13045-019-0760-3</a> Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar 19;140(6):883-99. doi: 10.1016/j.cell.2010.01.025. PMID: 20303878; PMCID: PMC2866629.   Murphy, M.P., Bayir, H., Belousov, V. et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nat Metab 4, 651–662 (2022). <a href="https://doi.org/10.1038/s42255-022-00591-z" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/s42255-022-00591-z</a> Geboes K, Riddell R, Öst A, et al A reproducible grading scale for histological assessment of inflammation in ulcerative colitis Gut 2000;47:404-409. Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1729-51. doi: 10.1158/1055-9965.EPI-14-0064. Epub 2014 Jun 24. PMID: 24962838; PMCID: PMC4155060. AOPWiki 2016-11-29T18:41:23

2024-02-28T06:33:44

Increase, Transforming growth factor-beta signaling

Activation of TGF-β signaling

Molecular

AOPWiki 2017-02-15T02:45:16

2026-02-11T05:39:19

Epithelial Mesenchymal Transition

EMT

Cellular

Epithelial-mesenchymal transition (EMT) is a phenomenon in which the cells transit from epithelial-like into mesenchymal-like phenotypes (Huan et al., 2022; Tanabe, 2017; Tanabe et al., 2015). In cancer, cells exhibiting EMT features contribute to metastasis and drug resistance. It is known that D-2-hydroxyglurate induces EMT (Guerra et al., 2017; Jia et al., 2018; Mishra et al., 2018; Sciacovelli & Frezza, 2017). D-2-hydroxyglurate, an inhibitor of Jumonji-family histone demethylase, increased the trimethylation of histone H3 lysine 4 (H3K4) in the promoter region of the zinc finger E-box-binding homeobox 1 (ZEB1), followed by the induction of EMT (Colvin et al., 2016). Wnt5a induces EMT and metastasis in non-small-cell lung cancer (Wang et al., 2017). EMT is related to Wnt/beta-catenin signaling and is important for treatment-resistant cancer (Tanabe et al., 2016). TGFbeta induces EMT (Wendt et al., 2010). ZEB is one of the critical transcription factors for EMT regulation (Zhang et al., 2015). SNAI1 (Snail) is an important transcription factor for cell differentiation and survival. The phosphorylation and nuclear localization of Snail1 induced by Wnt signaling pathways are critical for the regulation of EMT (Kaufhold & Bonavida, 2014). Transcription factors SNAI1 and TWIST1 induce EMT (Hodge et al., 2018) (Mani et al., 2008). It is suggested that Sp1, a transcription factor involved in cell growth and metastasis, is induced by cytochrome P450 1B1 (CYP1B1), and promotes EMT, which leads to cell proliferation and metastasis (Kwon et al., 2016). <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:601px"> <tbody> <tr> <td style="background-color:#eaf1dd; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:601px"> Biological state   An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri,  R.,  and  Neilson,  E.G.  2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.    EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a  cell through an EMT.   Biological compartment Cellular Role in General Biology: Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought  to herald the onset of the last stages of the multi-step process that  leads eventually to metastatic dissemination, with life-threatening  consequences.  There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell.  Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).  Pre-clinical experiments such as mice models and cell culture experiments  has demonstrated  that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as α-SMA, FSP1, vimentin,  and desmin (Yang,  J.,  and  Weinberg,  R.A.  2008). These cells  are seen at the invasive front  of primary tumors and are considered to be the cells that eventually  enter into subsequent steps of the invasion-metastasis cascade, i.e.,  intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth  of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001). An  apparent  paradox  comes  from  the  observation  that  the  EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological  level, the primary tumor from which they arose; accordingly,  they no longer exhibit the mesenchymal phenotypes ascribed to  metastasizing  carcinoma  cells.  Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during  the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of  disseminated cancer cells to undergo EMT likely reflects the local  microenvironments that they encounter after extravasation into  the parenchyma of a distant organ, quite possibly the absence of  the heterotypic signals they experienced in the primary tumor that  were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells. The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One  theory suggests that  the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008).  In  the case of many carcinomas, EMT-inducing signals emanating  from the tumor-associated stroma, notably HGF, EGF, PDGF,  and TGF-β, appear to be responsible for the induction or functional  activation  in  cancer  cells  of  a  series  of  EMT-inducing  transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M  et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo,  T.,  et  al.  2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of  intracellular signaling networks involving, among other signal- transducing  proteins,  ERK,  MAPK,  PI3K,  Akt,  Smads,  RhoB,  β-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos  as well as cell surface proteins such as β4 integrins, α5β1 integrin, and αVβ6 integrin (Tse,  J.C.,  and  Kalluri,  R.  2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang,  J.,  and  Weinberg,  R.A.  2008, Weinberg, R.A. 2008, Gupta, P.B  et al 2005, Yang,  J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..   </td> </tr> </tbody> </table>

Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010). <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:586px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:58px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:155px"> Method/ measurement referenc </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:73px"> Reliability   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:68px"> Strength of evidence   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:63px"> Assay fit for purpose   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:102px"> Repeatability/ reproducibility   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:67px"> Direct measure </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px"> Human cell line </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px"> qRT-PCR,cell viability assay, Western blotting,EdU incorporation assay </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px"> + </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> Strong </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px"> Human </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px"> IHC,micro array,qPCR, SNP array </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px"> + </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px"> Yes </td> </tr> </tbody> </table> <ul> <li style="text-align:left">EMT can be detected by immunostaining with pro-surfactant protein-C (pro-SPC) and N-cadherin in idiopathic pulmonary fibrosis (IPF) lung in vivo (Kim et al., 2006).</li> <li style="text-align:left">EMT can be detected by immunostaining with vimentin in lung alveola in vivo (Kim et al., 2006).</li> <li style="text-align:left">EMT can be detected as the increased level of the transcription factors, zinc finger E-box-binding homeobox (ZEB), Twist and Snail (Huang et al., 2022).</li> </ul>

The key event is applicaple in Homo sapiens: <ul> <li style="text-align:left">Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in Homo sapiens (Wang et al., 2017).</li> <li style="text-align:left">WNT2 expression lead to EMT induction in Homo sapiens (Zhou et al., 2016).</li> <li style="text-align:left">EMT is induced in cancer and involved in cancer metastasis in Homo sapiens (Suarez-Carmona, Lesage, Cataldo, & Gilles, 2017) (Du & Shim, 2016).</li> </ul> Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.

UBERON:0000062

UBERON organ

CL:0000066

CL epithelial cell

Not Specified Unspecific

Not Specified

Not Otherwise Specified

High

Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax, 64(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133">https://doi.org/10.1136/thx.2008.104133</a> Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. American Journal of Transplantation, 10(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x">https://doi.org/10.1111/j.1600-6143.2009.02953.x</a> Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610. Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70(9-10), 537-546. Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60. Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361. Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361. Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., . . . Ishii, H. (2016). Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Sci Rep, 6, 36289. doi:10.1038/srep36289 Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965 Fang, C. X., Ma, C. M., Jiang, L., Wang, X. M., Zhang, N., Ma, J. N., . . . Zhao, Y. D. (2018). p38 MAPK is Crucial for Wnt1- and LiCl-Induced Epithelial Mesenchymal Transition. Curr Med Sci, 38(3), 473-481. doi:10.1007/s11596-018-1903-4 Fidler, I. J., & Poste, G. (2008). The “seed and soil” hypothesis revisited. The lancet oncology, 9(8), 808. Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. Front Oncol, 7, 295. doi:10.3389/fonc.2017.00295 Gupta, P. B., Mani, S., Yang, J., Hartwell, K., & Weinberg, R. A. (2005, January). The evolving portrait of cancer metastasis. In Cold Spring Harbor symposia on quantitative biology (Vol. 70, pp. 291-297). Cold Spring Harbor Laboratory Press. Hanahan, D., and Weinberg, R.A. (2000). The hall- marks of cancer. Cell. 100:57–70. Hartwell, K. A., Muir, B., Reinhardt, F., Carpenter, A. E., Sgroi, D. C., & Weinberg, R. A. (2006). The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proceedings of the National Academy of Sciences, 103(50), 18969-18974. Jechlinger, M., Grünert, S., & Beug, H. (2002). Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. Journal of mammary gland biology and neoplasia, 7(4), 415-432. Hodge, D. Q., Cui, J., Gamble, M. J., & Guo, W. (2018). Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition. Sci Rep, 8(1), 841. doi:10.1038/s41598-018-19364-4 Huan, Z., Zhang, Z., Zhou, C., Liu, L., Huang, C. (2022). Epithelial-mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm. 2022 May 18;3(2):e144. doi: 10.1002/mco2.144 Jia, D., Park, J. H., Jung, K. H., Levine, H., & Kaipparettu, B. A. (2018). Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells, 7(3). doi:10.3390/cells7030021 Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation, 112(12), 1776-1784. Kaufhold, S., & Bonavida, B. (2014). Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res, 33, 62. doi:10.1186/s13046-014-0062-0 Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M. G., Brumwell, A. N., . . . Chapman, H. A. (2006). Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. PNAS, 103(35), 13180-13185. doi:10.1073/pnas.0605669103 Kwon, Y. J., Baek, H. S., Ye, D. J., Shin, S., Kim, D., & Chun, Y. J. (2016). CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/beta-Catenin Signaling via Sp1 Upregulation. PLoS One, 11(3), e0151598. doi:10.1371/journal.pone.0151598 Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., & Miyazono, K. (2008). Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. Journal of cell science, 121(20), 3317-3324. Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15. Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503. Mani, S. A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., ... & Weinberg, R. A. (2007). Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences, 104(24), 10069-10074. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., ... & Weinberg, R. A. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704-715. Medici, D., Hay, E. D., & Olsen, B. R. (2008). Snail and Slug promote epithelial-mesenchymal transition through β-catenin–T-cell factor-4-dependent expression of transforming growth factor-β3. Molecular biology of the cell, 19(11), 4875-4887. Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., . . . Ambs, S. (2018). ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest, 128(1), 323-340. doi:10.1172/JCI93815 Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. The Journal of cell biology, 182(2), 315-325. Sciacovelli, M., & Frezza, C. (2017). Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J, 284(19), 3132-3144. doi:10.1111/febs.14090 Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. cell, 113(6), 685-700. Smit, M. A., & Peeper, D. S. (2008). Deregulating EMT and senescence: double impact by a single twist. Cancer cell, 14(1), 5-7. Suarez-Carmona, M., Lesage, J., Cataldo, D., & Gilles, C. (2017). EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 11(7), 805-823. doi:10.1002/1878-0261.12095 Sun, J., Yang, X., Zhang, R., Liu, S., Gan, X., Xi, X., . . . Sun, Y. (2017). GOLPH3 induces epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in epithelial ovarian cancer. Cancer Med, 6(4), 834-844. doi:10.1002/cam4.1040 Taki, M., Verschueren, K., Yokoyama, K., Nagayama, M., & Kamata, N. (2006). Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. International journal of oncology, 28(2), 487-496. Tanabe, S. (2017). Molecular markers and networks for cancer and stem cells. J Embryol Stem Cell Res, 1(1). Tanabe, S., Kawabata, T., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Gene expression and pathway analysis of CTNNB1 in cancer and stem cells. World J Stem Cells, 8(11), 384-395. doi:10.4252/wjsc.v8.i11.384 Tanabe, S., Komatsu, M., Kazuhiko, A., Yokozaki, H., & Sasaki, H. (2015). Implications of epithelial-mesenchymal transition in gastric cancer. Translational Gastrointestinal Cancer, 4(4), 258-264 Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature reviews cancer, 2(6), 442-454. Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829. Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). doi:10.1042/BSR20171092 Weinberg, R. A. (2008). Twisted epithelial–mesenchymal transition blocks senescence. Nature cell biology, 10(9), 1021-1023. Wendt, M. K., Smith, J. A., & Schiemann, W. P. (2010). Transforming growth factor-beta-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene, 29(49), 6485-6498. doi:10.1038/onc.2010.377 Wik, E., Ræder, M. B., Krakstad, C., Trovik, J., Birkeland, E., Hoivik, E. A., ... & Salvesen, H. B. (2013). Lack of estrogen receptor-α is associated with epithelial–mesenchymal transition and PI3K alterations in endometrial carcinoma. Clinical Cancer Research, 19(5), 1094-1105. Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell, 14(6), 818-829. Yang, J., Mani, S. A., & Weinberg, R. A. (2006). Exploring a new twist on tumor metastasis. Cancer research, 66(9), 4549-4552. Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462. Zeisberg, M., Shah, A. A., & Kalluri, R. (2005). Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), 8094-8100. Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169. Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle, 14(4), 481-487. doi:10.1080/15384101.2015.1006048 Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. doi:10.1371/journal.pone.0160414 AOPWiki 2017-07-26T19:11:33

2024-04-24T00:44:46

Increase, Extracellular matrix deposition

Increase, ECM deposition

Tissue

ECM is a macromolecular structure that provides physical support to tissues and is essential for organ function. The composition of ECM is tissue specific and consists mainly of fibrous proteins, glycoproteins, and proteoglycans. The ECM in lung is compartmentalised to basement membrane and the interstitial space. Fibroblasts found in the interstitial space are the main sources of ECM in lung (White, 2015). Altered composition of ECM is observed in several lung diseases of inflammatory origin in humans including chronic obstructive pulmonary disease, asthma and idiopathic lung fibrosis. The composition and architecture of the ECM determines 1) the open sites of attachment that are available to cells, 2) the mechanical properties of the ECM and 3) the mechanical loading (breathing) experienced by the cells. Thus, changes in the ECM composition during the exaggerated wound healing process determines if an organism commits to fibrotic process or completes the wound healing (Blaauboer et al., 2014). Evidence for its perturbation in the context of pulmonary fibrosis: In lung fibrosis, an exaggerated amount of ECM is distributed in the alveolar parenchyma in a non-heterogenous manner, leading to lower spirometry readings implying occlusion of alveolar regions and reduced gas exchange. Collagen 1 and Collagen III are suggested to be the main components of the ECM in the thickened alveolar septa in fibrosis with other constituents such as fibronectin, elastin and tenacin C (Zhang et al., 1994; Hinz, 2006; Kuhn & McDonald, 1991; Crabb et al., 2006; Bensadoun et al., 1996; Klingberg et al., 2012; McKleroy et al., 2013). It is suggested that ECM composition dramatically changes during the fibrotic process. The early fibrotic process is characterised by collagen III deposition and collagen 1 predominates the later stages of the fibrosis. Excessive collagen production by myofibroblasts is necessary for the development of fibrosis (scarred tissue), with established areas of scar formation containing almost exclusively Type I collagen (Bateman et al., 1981; McKleroy et al., 2013; Zhang et al., 1994). Studies have demonstrated that while total collagen increases in IPF, there is also a shift toward the less elastic type I collagen, which contributes to the stiffness of the scar tissue within the lung (Nimni, 1983; Rozin et al., 2005; McKleroy et al., 2013). The fibrotic ECM contains characteristic accumulation of fibroblasts and myofibroblasts, which are the major contributors of ECM synthesised. The proliferation of fibroblasts and their differentiation into myofibroblasts is, in turn, guided by the composition and structure of the ECM. For example, studies have demonstrated that cytokines secreted in response to inflammation are capable of activating fibroblasts, and that these changes could cause alterations in the fibroblasts that lead to excessive proliferation and ECM deposition (Sivakumar et al., 2012; Wynn, 2011). In liver fibrosis, extracellular matrix (ECM) deposition is a critical hallmark. It represents the accumulation of fibrotic scar tissue due to excessive synthesis and reduced degradation of ECM components (e.g., collagen types I and III) (PMID: 34685739). This deposition disrupts liver architecture and impairs function. ECM deposition is considered a highly essential event for liver fibrosis progression because it marks the transition from reversible inflammation to irreversible fibrosis, it correlates with disease severity and progression to cirrhosis (PMID: 34685739). Experimental evidence often supports the essentiality, such as fibrosis models showing reduced ECM deposition when specific pathways (e.g., TGF-β or integrin signaling) are inhibited (PMID: 31362006). ECM deposition is a measurable KE using histological, biochemical, and imaging methods (e.g., Masson’s trichrome staining, hydroxyproline content, or MRI elastography, Red sirius).   Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells. 2021 Oct 15;10(10):2759. doi: 10.3390/cells10102759. PMID: 34685739; PMCID: PMC8534788. Fan W, Liu T, Chen W, Hammad S, Longerich T, Hausser I, Fu Y, Li N, He Y, Liu C, Zhang Y, Lian Q, Zhao X, Yan C, Li L, Yi C, Ling Z, Ma L, Zhao X, Xu H, Wang P, Cong M, You H, Liu Z, Wang Y, Chen J, Li D, Hui L, Dooley S, Hou J, Jia J, Sun B. ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice. Gastroenterology. 2019 Nov;157(5):1352-1367.e13. doi: 10.1053/j.gastro.2019.07.036. Epub 2019 Jul 27. PMID: 31362006.

qRT-PCR, Immunosorbant assays, and immunohistochemistry: The qRT-PCR, ELISA, and immunohistochemistry are routinely used to assess the levels of protein and mRNA levels. The various genes and proteins that are assessed include, collagen I, collagen III, elastin and tenacin C. Histological staining with stains such as Masson Trichrome, Picro-sirius red are used to identify the tissue/cellular distribution of collagen, which can be quantified using morphometric analysis both in vivo and in vitro. The assays are routinely used and are quantitative. Sircol Collagen Assay for collagen quantification: The Serius dye has been used for many decades to detect collagen in histology samples. The Serius Red F3BA selectively binds to collagen and the signal can be read at 540 nm (Chen & Raghunath, 2009; Nikota et al., 2017). Hydroxyproline assay: Hydroxyproline is a non-proteinogenic amino acid formed by the prolyl-4-hydroxylase. Hydroxyproline is only found in collagen and thus, it serves as a direct measure of the amount of collagen present in cells or tissues. Colorimetric methods are readily available and have been extensively used to quantify collagen using this assay (Chen & Raghunath, 2009; Nikota et al., 2017). Ex vivo and in vitro models of ECM deposition: No models currently exist which allow for in vitro assessment of ECM deposition. Using single, or co-cultures containing fibroblasts, the production of soluble ECM components can be assessed after exposure to a stressor of interest using either ELISA or qRT-PCR experiments as a proxy.

1. Bateman, E., Turner-Warwick, M. and Adelmann-Grill, B. (1981). Immunohistochemical study of collagen types in human foetal lung and fibrotic lung disease. Thorax, 36(9), pp.645-653. 2. Bensadoun, E., Burke, A., Hogg, J. and Roberts, C. (1996). Proteoglycan deposition in pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 154(6), pp.1819-1828. 3. Blaauboer M et al. Extracellular matrix proteins: A positive feedback loop in lung fibrosis. Matrix Biology, 2014, 34, 170-178 4. Chen, C. and Raghunath, M. (2009). Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis _ state of the art. Fibrogenesis & Tissue Repair, 2(1). 5. Crabb, R., Chau, E., Decoteau, D. and Hubel, A. (2006). Microstructural Characteristics of Extracellular Matrix Produced by Stromal Fibroblasts. Annals of Biomedical Engineering, 34(10), pp.1615-1627. 6. HINZ, B. (2006). Masters and servants of the force: The role of matrix adhesions in myofibroblast force perception and transmission. European Journal of Cell Biology, 85(3-4), pp.175-181. 7. Kuhn C, McDonald JA. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol. 1991;138(5):1257–1265. 8. Klingberg, F., Hinz, B. and White, E. (2012). The myofibroblast matrix: implications for tissue repair and fibrosis. The Journal of Pathology, 229(2), pp.298-309. 9. McKleroy, W., Lee, T. and Atabai, K. (2013). Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 304(11), pp.L709-L721. 10. Nikota, J., Banville, A., Goodwin, L., Wu, D., Williams, A., Yauk, C., Wallin, H., Vogel, U. and Halappanavar, S. (2017). 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. Particle and Fibre Toxicology, 14(1). 11. Nimni, M. (1983). Collagen: Structure, function, and metabolism in normal and fibrotic tissues. Seminars in Arthritis and Rheumatism, 13(1), pp.1-86. 12. Rozin, G., Gomes, M., Parra, E., Kairalla, R., de Carvalho, C. and Capelozzi, V. (2005). Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP). Histopathology, 46(4), pp.413-421. 13. Sivakumar, P., Ntolios, P., Jenkins, G. and Laurent, G. (2012). Into the matrix. Current Opinion in Pulmonary Medicine, 18(5), pp.462-469. 14. White, E. (2015). Lung Extracellular Matrix and Fibroblast Function. Annals of the American Thoracic Society, 12(Supplement 1), pp.S30- S33. 15. Wynn, T. (2011). Integrating mechanisms of pulmonary fibrosis. The Journal of Experimental Medicine, 208(7), pp.1339-1350. 16. Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994;145(1):114–125 AOPWiki 2018-01-05T13:12:18

2026-02-10T04:44:20

Pulmonary fibrosis

Organ

Pulmonary fibrosis is broadly defined as the thickening or scarring of lung tissue, due to excessive deposition of extracellular matrix. In the normal human lung, the nasopharynx and the conducting airways are mainly covered by epithelium composed of ciliated, mucous secreting cells in direct contact with the basement membrane with submucosal glands containing goblet, duct, and serous cells also contributing to the fluid balance and mucous production (Koval and Sidhaye, 2017). Within this epithelium, basal cells are found which are stimulated to proliferate and differentiate in response to injury (Koval and Sidhaye, 2017). Further down the lung, in the terminal bronchiole region, the epithelium does not contain submucosal glands, but instead contains club cells which produce pulmonary surfactant and can differentiate into bronchiolar or alveolar epithelial cells (AECs). Finally, in the terminal airspaces, the epithelium is made up entirely of type I and type II AECs. In between the two adjacent alveoli are two layers of alveolar epithelium resting on basement membrane, which consists of interstitial space, pulmonary capillaries, elastin and collagen fibres. Thus, the alveolar capillary membrane (ACM), where gas exchange takes place, is made up of the alveolar epithelium and alveolar endothelium (Gracey et al, 1968). In pulmonary fibrosis, damage to the pulmonary epithelium results in excessive deposition of collagen by constitutively activated myofibroblasts during the wound healing response. This causes a pronounced decrease in the number of capillaries within the alveolar septa with asymmetric deposition of collagen and cells between part of the surface of a capillary and the nearby alveolar lining. In areas where capillaries are not present, the ACM is occupied with collagen and cells.

In vivo, histopathological analysis is used for assessing fibrotic lung disease. Morphometric analysis of the diseased area versus total lung area is used to quantitatively stage the fibrotic disease. Although, some inconsistencies can be introduced during the analysis due to the experience of the individual scoring the disease, the histological stain, etc., a numerical scale with grades from 0 to 8, originally developed by Ashcroft et al., 1988 is assigned to indicate the amount of fibrotic tissue in histological samples. This scale is applied to diagnose lung fibrosis in both human and animal samples. Modifications to this scoring system were proposed (Hubner et al., 2008), which enables morphological distinctions thus enabling a better grading of the disease. Using the modified scoring system, bleomycin induced lung fibrosis in rats was scored as follows: Grade 0 – normal lung, Grade 1 – isolated alveolar septa with gentle fibrotic changes, Grade 2 – knot like formation in fibrotic areas in alveolar septa, Grade 3 – contiguous fibrotic walls of alveolar septa, Grade 4 – single fibrotic masses, Grade 5 – confluent fibrotic masses, Grade 6 – large contiguous fibrotic masses, Grade 7 – air bubbles and Grade 8 – fibrotic obliteration. Further morphometric analysis can be conducted to quantify the total disease area (Nikota et al., 2017). Lungs are formalin fixed and paraffin embedded such that an entire cross section of lung can be presented on a slide. The entire cross section is captured in a series of images using wide field light microscope. Areas of alveolar epithelium thickening and consolidated air space are identified. ImageJ software (freely available) is used to trace the total area (green line) and the diseased area (red line) imaged and quantified. The diseased area is equal to disease area/total area (Nikota et al., 2017). In vitro, there is no single assay that can measure the alveolar thickness. However, a combination of assays spanning various KEs described above provide a measure of the extent of fibrogenesis potential of tested substances. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays (ELISA) measuring increased collagen, Transforming growth factor beta 1 (TGF-β1) and various pro-inflammatory mediators are used as sensitive markers of potential of substances to induce the adverse outcome of lung fibrosis.

UBERON:0002048

UBERON lung

High Unspecific

High

Adults

High High High 1. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988 Apr;41(4):467-70. doi: 10.1136/jcp.41.4.467. 2. Gracey DR, Divertie MB, Brown AL Jr. Alveolar-capillary membrane in idiopathic interstitial pulmonary fibrosis. Electron microscopic study of 14 cases. Am Rev Respir Dis. 1968 Jul;98(1):16-21. doi: 10.1164/arrd.1968.98.1.16. 3. Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008 Apr;44(4):507-11, 514-7. doi: 10.2144/000112729.  4. Koval M, Sidhaye VK. Introduction: The Lung Epithelium. In: Sidhaye VK, Koval M, editors. Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease. Boston: Academic Press; 2017. p. xiii-xviii. Elsevier. 5. 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.  AOPWiki 2017-07-26T19:13:54

2023-05-12T17:09:50

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AOPWiki 2026-09-29T00:42:20

2026-09-29T00:42:20

<upstream-id>36e561c9-eab6-4fcb-8118-8e9197c8cf3c</upstream-id> <downstream-id>517b69b4-5044-4cc0-88aa-f81f3774de8d</downstream-id>

AOPWiki 2026-09-29T00:43:44

2026-09-29T00:43:44

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AOPWiki 2018-03-18T09:49:43

2018-03-18T09:49:43

<upstream-id>f1a705d0-68d8-4b0f-a515-9ec9af04f25e</upstream-id> <downstream-id>30e97080-bc81-4b08-b989-28f811086a56</downstream-id>

AOPWiki 2026-09-29T00:44:23

2026-09-29T00:44:23

<upstream-id>30e97080-bc81-4b08-b989-28f811086a56</upstream-id> <downstream-id>d7b145e9-94da-4289-82c0-6ee9f5151724</downstream-id> Fibrosis by definition is the end result of a healing process. It involves a series of lung remodelling and reorganisation events leading to permanent alteration in the lung architecture and a fixed scar tissue or fibrotic lesion (Wallace WA, 2007). Excessive deposition of ECM or collagen is the hallmark of this disease and there is ample evidence to support this KER (Fukuda 1985, Meyer 2017, Richeldi 2017, Thannickal 2004, Zisman 2005).

By definition, pulmonary fibrosis is characterized by excessive deposition of extracellular matrix and destruction of native lung architecture (Fukuda 1985, Richeldi 2017, Thannickal 2004). Thus, the plausibility of this association is undisputed.

Excessive ECM deposition is the defining characteristic of pulmonary fibrosis, and the evidence to support this relationship is unequivocal. (Meyer 2017, Thannickal 2004, Zisman 2005).

Since the adverse outcome of lung fibrosis involves multiple cell types, cell - cell interactions and cell–biomolecule interactions, it is difficult to recapitulate the entire process in one model. Therefore, an integrated approach, such as one consisting of cell systems that assess individual KEs and quantitative relationships between the KEs, is needed to predict the AO in humans.

High

Adult

High High High

Humans (Zisman 2005, Meyer 2017), rats (Williamson 2015), mice (Williamson 2015).

<ol> <li>Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG. Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol. 1985;118(3):452–475.</li> <li>Meyer K. C. (2017). Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert review of respiratory medicine, 11(5), 343–359. <a href="https://doi.org/10.1080/17476348.2017.1312346" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1080/17476348.2017.1312346</a></li> <li>Richeldi, L., Collard, H. R., & Jones, M. G. (2017). Idiopathic pulmonary fibrosis. Lancet (London, England), 389(10082), 1941–1952. <a href="https://doi.org/10.1016/S0140-6736(17)30866-8" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/S0140-6736(17)30866-8</a></li> <li>Thannickal, V. J., Toews, G. B., White, E. S., Lynch, J. P., 3rd, & Martinez, F. J. (2004). Mechanisms of pulmonary fibrosis. Annual review of medicine, 55, 395–417. <a href="https://doi.org/10.1146/annurev.med.55.091902.103810" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1146/annurev.med.55.091902.103810</a></li> <li>Wallace, W., Fitch, P., Simpson, A. and Howie, S. (2006). Inflammation-associated remodelling and fibrosis in the lung - a process and an end point. International Journal of Experimental Pathology, 88(2), pp.103-110</li> <li>Williamson, J. D., Sadofsky, L. R., & Hart, S. P. (2015). The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Experimental lung research, 41(2), 57–73. <a href="https://doi.org/10.3109/01902148.2014.979516" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3109/01902148.2014.979516</a></li> <li>Zisman, D. A., Keane, M. P., Belperio, J. A., Strieter, R. M., & Lynch, J. P., 3rd (2005). Pulmonary fibrosis. Methods in molecular medicine, 117, 3–44. <a href="https://doi.org/10.1385/1-59259-940-0:003" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1385/1-59259-940-0:003</a></li> </ol> AOPWiki 2018-01-16T09:35:18

2021-12-06T16:55:21

Activation of Transient Receptor Potential A1 (TRPA1) Leading to Pulmonary Fibrosis

TRPA1 Activation Leading to Pulmonary Fibrosis

Yuan Luo

Luo Yuan, Lin Xueyang, Sun Yixian, Wang Yongan, Du Xianli, Feng Wenya

2.8

Abstract: Pulmonary fibrosis is a chronic, irreversible lung disease characterized by excessive extracellular matrix (ECM) deposition and structural destruction of the lungs, closely associated with environmental stressors. Traditional research has primarily focused on the role of classical pathways such as TGF-β/Smad in pulmonary fibrosis, yet the mechanism by which environmental stressors initiate fibrosis remains incompletely elucidated. Transient Receptor Potential Ankyrin 1 (TRPA1), a widely expressed ion channel in lung epithelial cells, fibroblasts, and immune cells, acts as a direct sensor of environmental stress. Its activation triggers downstream calcium signaling and inflammatory responses, but its initiating role in pulmonary fibrosis and association with classical pathways have not been systematically integrated into mechanistic frameworks. Existing OECD AOP Wiki networks also lack a dedicated pathway for TRPA1-mediated pulmonary fibrosis. Therefore, constructing an AOP for TRPA1 activation-induced pulmonary fibrosis is of great significance for revealing novel mechanisms of environmental stressor-induced fibrosis and filling gaps in the existing pulmonary fibrosis AOP network. Background: Pulmonary fibrosis is a potentially fatal respiratory disease characterized by the accumulation of interstitial scar tissue, leading to the loss of alveolar function, destruction of normal lung architecture, and impaired respiratory function. Adverse Outcome Pathways (AOP) provide a framework for testing and evaluating pulmonary fibrosis. However, to enhance the applicability of AOPs in regulatory environments, further development of the pulmonary fibrosis AOP framework is necessary. This study develops an AOP for pulmonary fibrosis induced by TRPA1 activation, aimed at predicting all compounds highly related to this AOP. Additionally, this study identifies core Key Events (KEs) shared across different AOPs to facilitate further development of the AOP. Existing OECD AOP Wiki networks also lack a dedicated pathway for TRPA1-mediated pulmonary fibrosis. Therefore, constructing an AOP for TRPA1 activation-induced pulmonary fibrosis is of great significance for revealing novel mechanisms of environmental stressor-induced fibrosis and filling gaps in the existing pulmonary fibrosis AOP network.

adjacent

High

High adjacent

Moderate

Moderate adjacent

High

High adjacent

Moderate

High adjacent

High

<table cellspacing="0" class="17" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:90px"> Type (Event ID) </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:113px"> Title </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:354px"> Description </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:364px"> Support for the essentiality of the KE </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:90px"> MIE (1215) </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:113px"> Activation of TRPA1 </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:354px"> The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism.  TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure1. The TRPA1 channel was first successfully isolated in human lung fibroblasts, and it was found to have a relatively concentrated distribution in the lungs and respiratory tract. It is also involved in various acute and chronic inflammatory processes of lung diseases and may even play a core role in the progression and/or prevention of pulmonary fibrosis2. </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:364px"> <a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Achanta+S&cauthor_id=32892378">Satyanarayana Achanta</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Jordt+SE&cauthor_id=32892378">Sven-Eric Jordt</a> (2020)3reported TRPA1 play a crucial role in complex pulmonary pathophysiologic events including, increased intracellular calcium levels, signal transduction, recruitment of proinflammatory cells, neurogenic inflammatory pathways and fibrosis. There is no doubt that TRPA1 localized in the sensory network contribute to airway neurogenic inflammation, and emerging evidence underlines the role of nonneuronal TRPA1 in orchestrating inflammation and repair in the respiratory tract4.   </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:90px"> KE1 (149) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:113px"> Increase inflammation </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:354px"> Inflammatory cytokines refer to a variety of cytokines involved in the inflammatory response. Among the many inflammatory cytokines, TNF-α, IL-1β, IL-6, TGF-β, IL-8, IL-l0, etc5. TNF-α is the earliest and most important inflammatory mediator in the process of inflammatory response, which can activate neutrophils and lymphocytes, increase the permeability of vascular endothelial cells, regulate the metabolic activity of other tissues, and promote the synthesis and release of other cytokines6. IL-6 can induce B-cell differentiation and antibody production, and induce T-cell activation, proliferation and differentiation, and participate in the body's immune response, which is a promoter of inflammatory response7. </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:364px"> Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1β (IL-1β). IL-1β instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-β)8. RNA sequencing showed that the tumor necrosis factor alpha (TNFα) signaling pathway and transforming growth factor beta (TGFβ) signaling pathway were consistently activated, potentially contributing to the development of inflammation and fibrosis9. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:none; border-top:1px solid #9bbb59; vertical-align:center; width:90px"> KE2 (1271) </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:113px"> Activation of TGF-β signaling </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:354px"> The transforming growth factor-β (TGF-β) is the prototype of the TGF-β family of growth and differentiation factors, which is encoded by 33 genes in mammals and comprises homo- and heterodimers. This review introduces the reader to the TGF-β family with its complexity of names and biological activities. It also introduces TGF-β as the best-studied factor among the TGF-β family proteins, with its diversity of roles in the control of cell proliferation and differentiation, wound healing and immune system, and its key roles in pathology, for example, skeletal diseases, fibrosis, and cancer10. </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:364px"> In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-β can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition (EMT) as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis11. TGF-β is a central regulator involved in EMT and pulmonary fibrosis. E3 ubiquitin ligases regulate TGF-β-Smad pathway-mediated EMT via the ubiquitin-proteasome pathway12. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:90px"> KE3 (1457) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:113px"> Epithelial mesenchymal transition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:354px"> The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT13. </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:364px"> Using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production14. Epithelial cells can undergo a process called epithelial-mesenchymal transition, in which they acquire a more mesenchymal-like phenotype and contribute directly to fibroblast activation and ECM deposition15. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:90px"> KE4 (1501) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:113px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:354px"> Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions16. </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:364px"> Pulmonary fibrosis (PF) is characterized by an increase in collagen synthesis and deposition of extracellular matrix. Several factors, including transforming growth factor-β1 (TGF-β1), mothers against decapentaplegic homolog family proteins (Smad), and alpha-smooth muscle actin (α-SMA) trigger extracellular matrix (ECM) accumulation, fibroblast to myofibroblasts conversion, and epithelial-to-mesenchymal-transition (EMT) leading to PF 17. We demonstrated that the exposure of PM2.5 could enhance the ERS induced-autophagy-mediated Cav-1 degradation, thus activating the TGF-β1/Smad3 axis to promote pneumonocytes apoptosis and overproduction of extracellular matrix (ECM), finally aggravating PF18. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:90px"> AO (1458) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:113px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:354px"> Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs19.  </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:364px">   </td> </tr> </tbody> </table>

<table cellspacing="0" class="16" style="border-collapse:collapse; border:none; width:100.0000%"> <tbody> <tr> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:185px"> Upstream event </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:115px"> Relationship type </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:254px"> Downstream events </td> <td style="background-color:#eeece1; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:371px"> Evidence from the literature </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px"> Activation of TRPA1 </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> adjacent </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:254px"> Increase inflammation </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:371px"> TRPA1 is expressed in a large subset of sensory nerves, where it integrates numerous noxious stimuli. In non-neuronal cells, TRPA1 also acts as nociceptive sensors and potentiate the inflammatory process20. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:254px"> Activation of TGF-β signaling </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:371px"> The lack of TRPA1 in cultured ocular fibroblasts attenuated expression of TGF-β1, interleukin-6, and α-smooth muscle actin, a myofibroblast the marker, but suppressed the activation of Smad3, p38 MAPK, ERK, and JNK.The responsible mechanism may include the inhibition of TGF-β1-signaling cascades in fibroblasts by attenuated TRPA1 signaling21. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:none; border-top:1px solid #9bbb59; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:254px"> Epithelial mesenchymal transition </td> <td style="border-bottom:1px solid #9bbb59; border-left:1px solid black; border-right:1px solid black; border-top:1px solid #9bbb59; vertical-align:center; width:371px"> Transient depotentiation of TRPA1 by siRNA is sufficient to attenuate the downstream signalling pathway of FGFR2c and consequently affect EMT22. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:254px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:center; width:371px"> The activation of transient receptor potential ankyrin 1 (TRPA1) was claimed to be a risk factor in osteoarthritis by causing inflammation and extracellular matrix degradation23. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> Targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition24. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px"> Increase inflammation </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Activation of TGF-β signaling </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1β (IL-1β). IL-1β instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-β)8. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Epithelial mesenchymal transition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> EMT also plays a key role in wound healing processes, which are mediated by inflammatory cells and fibroblasts.  Wound healing follows four distinct and successive phases characterized by haemostasis, inflammation, cell proliferation and finally tissue remodeling25. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> The effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors26. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> Idiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin suppressed BLM-induced inflammation via NF-κB/NLRP3 pathway both in vivo and in vitro. Scutellarin suppressed inflammation and EMT in BLM-induced pulmonary fibrosis through NF-κB/NLRP3 signaling27. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px"> Activation of TGF-β signaling </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Epithelial mesenchymal transition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> it was demonstrated that transforming growth factor (TGF)-beta induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis28. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> Overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer29. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> PFD alleviated pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways, which might further improve the action mechanism of anti-fibrosis effect of PFD30. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px"> Epithelial mesenchymal transition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> In vivo studies revealed that SiNPs-induced pulmonary fibrosis mainly manifested as EMT trans-differentiation in airway epithelial cells, which subsequently led to excessive deposition of extracellular matrix (ECM)31. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> non-adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF).  Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. Activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb32. </td> </tr> <tr> <td style="background-color:#ffffff; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; vertical-align:center; width:185px"> Increased extracellular matrix deposition </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:115px"> adjacent </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:254px"> Pulmonary fibrosis </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:center; width:371px"> It progresses with the recruitment of fibroblasts and myofibroblasts that contribute to the accumulation of extracellular matrix (ECM) proteins, leading to the loss of compliance and alveolar integrity, compromising the gas exchange capacity of the lung33. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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