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Relationship: 2959

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Interaction with the lung cell membrane leads to Systemic acute phase response

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Interaction with the lung cell membrane

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Systemic acute phase response

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Substance interaction with lung resident cell membrane components leading to atherosclerosis via acute phase response	non-adjacent	High	Moderate	Ulla Vogel (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

This KER presents the association between the interaction of stressors with the lung resident cell membrane components (Key event 1495) and the induction of systematic acute phase response (Key event 1439). The evidence of the KER presented is based on animal studies (mice), controlled human studies and epidemiological studies.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Targeted literature search focusing on humans and mice.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility is high. Pulmonary inflammation occurs when stressors interact with the airways (Moldoveanu et al., 2009) and acute phase response is induced during a subsequent inflammatory response (Gabay & Kushner, 1999). It has been shown (see table below) that exposure to many different stressors produces a dose-dependent increase of acute phase proteins in blood [i.e. C-reactive protein (CRP) and serum amyloid A (SAA)] in humans and mice.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Inhaled substances including ambient air pollution, lipopolysaccharide or different particulates will interact with the respiratory system, including the cells. Studies showing that inhalation exposure to various agents leads to systemic acute phase response are considered evidence for this KER, even if the specific interaction between the substance and the respiratory system has not been investigated.

The table below presents the evidence for this KER. Exposure through the respiratory system (inhalation or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components (Key event 1495), while systemic acute phase response is measured as the concentration of acute phase protein in blood plasma or serum (Key event 1439). The table describes animal studies, where pulmonary exposure to various particles, lipopolysaccharide or the acute phase protein serum amyloid A to increased blood levels of the acute phase protein serum amyloid A as compared to controls. The table also describes controlled human exposure studies, where human volunteers are exposed to various particulate exposures or to clean air, where exposure to particles leads to increased blood levels of acute phase proteins C-reactive protein and/or Serum Amyloid A. Finally, the table also includes an epidemiological study showing association between ambient air pollution assessed as PM2.5 and blood levels of C-reactive protein.

Both animal studies and controlled human studies show dose-response relationship between pulmonary exposure and systemic acute phase response (Saber et al., 2013) (Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015) (Bengtson et al., 2017) (Monse et al., 2018) (Zhang et al., 2017).

Species	Stressor	Substance interaction with lung residents cell membrane components	Systemic acute phase response	Reference
Mouse	Carbon black nanoparticles	Yes, intratracheal instillation of 162 µg.	Yes, significant increase of plasma serum amyloid A (SAA) at 1 and day 28 after exposure.	(Bourdon et al., 2012)
Mouse	Multiwalled carbon nanotubes	Yes, intratracheal instillation of 18, 54 and 128 µg.	Yes, increased levels of plasma SAA3 after 1 day, with 128 µg.	(Saber et al., 2013)
Mouse	Multiwalled carbon nanotubes (referred as CNT_small)	Yes, intratracheal instillation of 18, 54 and 162 µg.	Yes, increased plasma SAA3 1, 3 and 28 days after exposure to 162 µg, and 3 days after exposure to 18 and 54 µg.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Multiwalled carbon nanotubes (referred as CNT_large)	Yes, 18, 54 and 162 µg. intratracheal instillation of	Yes, increased plasma SAA3 1 and 3 days after exposure to 162 µg, and 3 days after exposure to 54 µg.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Graphene oxide	Yes, intratracheal instillation of 18, 54 and 162 µg.	Yes, increased SAA3 plasma levels 3 days after exposure to 54 and 162 µg.	(Bengtson et al., 2017)
Mouse	Multiwalled carbon nanotubes	Yes, intratracheal instillation of 54 µg.	Yes, increased SAA1/2 and SAA3 plasma levels 1 day after exposure to. No change in SAA1/2 and SAA3 28 and 92 days after exposure.	(Poulsen et al., 2017)
Mouse	Multiwalled carbon nanotubes	Yes, intratracheal instillation of 6, 18 and 54 µg.	Yes, increased SAA1/2 plasma levels 1 day after exposure. No change in SAA1/2 28 and 92 days after exposure. Increased SAA3 plasma levels 1 days after exposure. Increased SAA3 plasma levels 28 and 92 days after exposure.	(Poulsen et al., 2017)
Mouse	Carbon black	Yes, intratracheal instillation of 162 µg.	Yes, increased SAA3 plasma levels 1 days after exposure. No change in SAA3 28 and 92 days after exposure. No change in SAA1/2 plasma levels.	(Poulsen et al., 2017)
Mouse	Particulate matter from non-commercial airfield	Yes, intratracheal instillation of 6, 18 and 54 µg.	Yes, increased plasma SAA3 levels after exposure to 54 µg.	(Bendtsen et al., 2019)
Mouse	Diesel exhaust particles	Yes, intratracheal instillation of 18, 54 and 54 µg.	Yes, increased plasma SAA3 levels after exposure to 54 µg.	(Bendtsen et al., 2019)
Mouse	Nanofibrilated celluloses (FINE NFC, BIOCID FINE NFC and AS)	Yes, intratracheal instillation of 6 and 18 µg.	FINE NFC increased plasma SAA3 1 day after exposure to 6 and 18 µg, while AS increased SAA3 after exposure to 18 µg. After 28 days, only 6 µg of FINE NFC increased plasma SAA3.	(Hadrup, Knudsen, et al., 2019)
Mouse	Copper oxide	Yes, intratracheal instillation of 2, 6 and 12 µg.	Yes, increased plasma SAA1/2 level after exposure to 6 µg.	(Gutierrez et al., 2023)
Mouse	Tin dioxide	Yes, intratracheal instillation of 54 and 162 µg.	Yes, increased plasma SAA3 after exposure to 162 µg.	(Gutierrez et al., 2023)
Mouse	Titanium dioxide	Yes, intratracheal instillation of 162 µg.	Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg.	(Gutierrez et al., 2023)
Mouse	Carbon black	Yes, intratracheal instillation of 162 µg.	Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg.	(Gutierrez et al., 2023)
Mouse	Singlewalled carbon nanotubes	Yes, pharyngeal aspiration of 40 µg.	Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure.	(Erdely et al., 2011)
Mouse	Multiwalled carbon nanotubes	Yes, pharyngeal aspiration of 40 µg.	Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure. No changes after 28 days.	(Erdely et al., 2011)
Mouse	Serum amyloid A	Yes, intratracheal instillation (2 µg) once a week for 10 weeks.	Yes, increased levels of endogenous serum SAA3.	(Christophersen et al., 2021)
Human	Welding fumes	Yes, median exposure to welders (PM_2.5) was 1.66 mg/m³ and 0.04 mg/m³ for controls, during 5.3 h.	No changes in serum C reactive protein (CRP) 6 hours after exposure, but significantly increased serum CRP levels 16 hours after welding.	(Kim et al., 2005)
Human	Wood smoke	Yes, 4h exposure to 240-280 µg/m³.	Yes, significant increase in blood SAA after exposure, and 3 and 20 h after exposure, no change in CRP.	(Barregard et al., 2006)
Human	Brazing fumes	Yes, 6h exposure to 1.4, 2 and 2.5 mg/m³.	Yes, increased blood CRP 24h after exposure to 2 and 2.5 mg/m³.	(Brand et al., 2014)
Human	Fumes from welding aluminium	Yes, 6h exposure to 2.5 mg/m³.	Yes, significantly increased blood CRP 24 after exposure. No change after exposure nor a week after exposure.	(Hartmann et al., 2014)
Human	Fumes from welding zinc coated materials	Yes, 6h exposure to 2.5 mg/m³.	Yes, significantly increased blood CRP 24 after exposure. No change after exposure nor a week after exposure.	(Hartmann et al., 2014)
Human	Traffic related particulate matter	Yes, exposure during work hours.	Yes, serum CRP and SAA were significantly and positively associated with increases in exposure.	(Meier et al., 2014)
Human	Fumes from brazing galvanized steel, using aluminum bronze wire	Yes, 6h exposure to 2.5 mg/m³.	Yes, significant increase in serum CRP and SAA 29 h after exposure. No change 6 nor 10 h after exposure.	(Baumann et al., 2016)
Human	Fumes from welding galvanized steel and aluminum, using zinc wire	Yes, 6h exposure to 2 mg/m³.	Yes, significant increase in serum CRP and SAA 29 h after exposure. No change 6 nor 10 h after exposure.	(Baumann et al., 2016)
Human	Fumes from brazing galvanized steel using zinc wire	Yes, 6h exposure to 2 mg/m³.	Yes, significant increase in serum CRP 29 h after exposure. No change 6 nor 10 h after exposure.	(Baumann et al., 2016)
Human	Dust from pulp and paper mill	Yes, exposure during working hours.	Yes, blood CRP, SAA and fibrinogen were significantly and positively associated with the exposure.	(Westberg et al., 2016)
Human	Zinc welding fumes	Yes, 6h exposure to 2.5 mg/m³	Yes, significant plasma SAA increase at 24 h. No effect at 6h.	(Baumann et al., 2018)
Human	Copper welding fumes	Yes, 6h exposure to 2.5 mg/m³	Yes, significant plasma SAA increase at 24 h. No effect at 6h.	(Baumann et al., 2018)
Human	Zinc and copper welding fumes	Yes, 6h exposure to 2.5 mg/m³	Yes, significant plasma SAA increase at 24 h. No effect at 6h.	(Baumann et al., 2018)

Additional empirical evidence can be found in the following links: Additional evidence KER 2959_1 and Additional evidence KER 2959_2.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

In animal studies using well-characterized materials, physicochemical characteristics such as size, surface area, surface functionalization, shape, and solubility, affect the magnitude and duration of the acute phase response in mice (Bengtson et al., 2017; Gutierrez et al., 2023; Poulsen et al., 2017).

In controlled human studies, an increase in CRP and/or SAA was observed after exposure to particulate matter (Baumann et al., 2018; Monse et al., 2018; Monse et al., 2021; Walker et al., 2022; Wyatt et al., 2020). However, in some human studies, no exposure-related acute phase response was detected (Andersen, Saber, Clausen, et al., 2018; Andersen, Saber, Pedersen, et al., 2018), maybe due to a low level of exposure (Andersen et al., 2019). The lack of exposure-related systemic acute phase response could be caused by low exposure levels or limited statistical power.

The table below presents inconsistencies for this KER, where substance interaction with lung resident cell membrane components has occurred, while systemic acute phase response was not observed. Exposure through the respiratory system (inhalation or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components, while systemic acute phase response is measured as the concentration of acute phase protein in blood plasma or serum.

Species	Stressor	Substance interaction with lung residents cell membrane components	Systemic acute phase response	Reference
Mouse	Diesel exhaust particles	Yes, inhalation of 20 mg/m³ for 90 min, in 4 consecutive days.	No effect.	(Saber et al., 2009, 2013)
Mouse	Carbon black	Yes, inhalation of 20 mg/m³ for 90 min, in 4 consecutive days.	No effect.	(Saber et al., 2009, 2013)
Mouse	Reduced graphene oxide	Yes, intratracheal instillation of 18, 54 and 162 µg.	No, no change in SAA3 plasma concentration 3 days after exposure.	(Bengtson et al., 2017)
Mouse	Crocidolite	Yes, intratracheal instillation of 6 and 18 µg.	No change in SAA1/2 nor SAA3 plasma levels.	(Poulsen et al., 2017)
Mouse	Particulate matter from commercial airport	Yes, intratracheal instillation of 6, 18 and 54 µg.	No change in plasma SAA3.	(Bendtsen et al., 2019)
Mouse	Carbon black	Yes, intratracheal instillation of 54 µg.	No change in plasma SAA3.	(Bendtsen et al., 2019)
Mouse	Uncoated zinc oxide nanoparticles	Yes, intratracheal instillation of 0.2, 0.7 and 2 µg.	No effect on plasma SAA3.	(Hadrup, Rahmani, et al., 2019)
Mouse	Coated zinc oxide nanoparticles	Yes, intratracheal instillation of 0.2, 0.7 and 2 µg.	No effect on plasma SAA3.	(Hadrup, Rahmani, et al., 2019)
Mouse	Zinc oxide	Yes, intratracheal instillation of 0.7 and 2 µg.	No change in plasma SAA3 or SAA1/2 levels.	(Gutierrez et al., 2023)
Mouse	Aluminum oxide	Yes, intratracheal instillation of 18 and 54 µg.	No change in plasma SAA3 or SAA1/2 levels.	(Gutierrez et al., 2023)
Human	Particulate matter and gas from fire extinguishing exercise	Yes, exposure during training exercises.	No change was observed on blood CRP or SAA levels.	(Andersen, Saber, Clausen, et al., 2018)
Human	Gas and particulate matter from firefighting activities	Yes, exposure during firefighting.	No change was observed on blood CRP or SAA levels.	(Andersen, Saber, Pedersen, et al., 2018)
Human	Diesel exhaust	Yes, 6h per day for 3 days.	No change was observed on blood CRP or SAA levels.	(Andersen et al., 2019)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The interaction of insoluble nanomaterials with the lungs (Key event 1495) (measured in dosed surface area: dosed mass multiply by specific surface area) is correlated to serum amyloid A (SAA)3 and SAA1/2 plasma levels (Key event 1439) and the responses show a linear regression, in female C57BL/6J mice 1 day after intratracheal instillation (Gutierrez et al., 2023) (Figure 1 and Figure 2).

The Pearson’s correlation coefficient was 0.92 (p <0.001) between log-transformed dosed surface area (dosed mass multiply by specific surface area) and log-transformed SAA3 plasma levels (Figure 1). The linear regression formula obtained was Log SAA3 = 0.9459 *Log Dosed surface area – 2.854 (p=0.01). In the case SAA1/2, the correlation coefficient was 0.83 (p<0.05) between log-transformed dosed surface area and log-transformed SAA1/2 plasma levels was, and the linear regression formula was Log SAA1/2 = 0.6368 *Log Dosed surface area +0.09524 (p=0.01) (Figure 2) (Gutierrez et al., 2023).

Figure 1. Correlations between pulmonary dosed surface area and SAA3 protein in plasma, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

Figure 2. Correlations between pulmonary dosed surface area and SAA1/2 protein in plasma, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The experimental evidence suggests that a systemic acute phase response occurs relatively fast (hours to 1 day) following pulmonary exposure. Furthermore, epidemiological evidence suggests that during chronic exposure to air pollution, systemic acute phase response is increased in parallel.

In mice, increased serum amyloid A (SAA) protein levels were observed 1 and 3 days after most exposures in a dose-dependent manner (Bourdon et al., 2012; Hadrup, Knudsen, et al., 2019; Poulsen et al., 2017; Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015). For insoluble particles and fibers, more long-lasting systemic acute phase responses were observed at high dose levels (Bourdon et al., 2012; Hadrup, Knudsen, et al., 2019; Poulsen et al., 2017; Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015).

For highly soluble metal oxides, a transient systemic acute phase response is observed (Gutierrez et al., 2023). ZnO is an example of a metal oxide which is highly soluble under acidic conditions and therefore undergo dissolution in the lysosomes of macrophages in the lung following pulmonary exposure. In a controlled human study, volunteers were exposed to ZnO for 2 hours at 3 different dose levels. Immediately after end of exposure, blood levels of systemic acute phase proteins SAA and C-reactive protein (CRP) were unaffected by exposure (Monse et al., 2021). 22 h and 2 days post-exposure, , SAA and C-reactive protein were dose-dependently increased compared to exposure to clean air. Three days post-exposure, SAA and CRP levels had returned to base-line. After exposure to zinc oxide, copper oxide or a mix both, SAA levels were elevated 24h after exposure in humans, but not 6h after exposure (Baumann et al., 2018). In an epidemiological study, a positive correlation was observed between air pollution measured as PM2.5 and CRP in blood (Zhang et al., 2017). This suggests that the systemic acute phase response is chronically increased during chronic exposures (for example by living in areas with high levels of air pollution).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Systemic acute phase response is measured as elevation of acute phase proteins in humans (both sexes) (mainly C reactive protein and serum amyloid A), and serum amyloid A in mice has been shown after exposure to several stressors (see Empirical evidence). This KER is applicable at all life stages.

References

List of the literature that was cited for this KER description. More help

Andersen, M. H. G., Frederiksen, M., Saber, A. T., Wils, R. S., Fonseca, A. S., Koponen, I. K., . . . Vogel, U. (2019). Health effects of exposure to diesel exhaust in diesel-powered trains. Part Fibre Toxicol, 16(1), 21. doi:10.1186/s12989-019-0306-4

Andersen, M. H. G., Saber, A. T., Clausen, P. A., Pedersen, J. E., Lohr, M., Kermanizadeh, A., . . . Vogel, U. (2018). Association between polycyclic aromatic hydrocarbon exposure and peripheral blood mononuclear cell DNA damage in human volunteers during fire extinction exercises. Mutagenesis, 33(1), 105-115. doi:10.1093/mutage/gex021

Andersen, M. H. G., Saber, A. T., Pedersen, J. E., Pedersen, P. B., Clausen, P. A., Lohr, M., . . . Moller, P. (2018). Assessment of polycyclic aromatic hydrocarbon exposure, lung function, systemic inflammation, and genotoxicity in peripheral blood mononuclear cells from firefighters before and after a work shift. Environ Mol Mutagen, 59(6), 539-548. doi:10.1002/em.22193

Barregard, L., Sallsten, G., Gustafson, P., Andersson, L., Johansson, L., Basu, S., & Stigendal, L. (2006). Experimental exposure to wood-smoke particles in healthy humans: effects on markers of inflammation, coagulation, and lipid peroxidation. Inhal Toxicol, 18(11), 845-853. doi:10.1080/08958370600685798

Baumann, R., Gube, M., Markert, A., Davatgarbenam, S., Kossack, V., Gerhards, B., . . . Brand, P. (2018). Systemic serum amyloid A as a biomarker for exposure to zinc and/or copper-containing metal fumes. J Expo Sci Environ Epidemiol, 28(1), 84-91. doi:10.1038/jes.2016.86

Baumann, R., Joraslafsky, S., Markert, A., Rack, I., Davatgarbenam, S., Kossack, V., . . . Gube, M. (2016). IL-6, a central acute-phase mediator, as an early biomarker for exposure to zinc-based metal fumes. Toxicology, 373, 63-73. doi:10.1016/j.tox.2016.11.001

Bendtsen, K. M., Brostrom, A., Koivisto, A. J., Koponen, I., Berthing, T., Bertram, N., . . . Vogel, U. (2019). Airport emission particles: exposure characterization and toxicity following intratracheal instillation in mice. Part Fibre Toxicol, 16(1), 23. doi:10.1186/s12989-019-0305-5

Bengtson, S., Knudsen, K. B., Kyjovska, Z. O., Berthing, T., Skaug, V., Levin, M., . . . Vogel, U. (2017). Differences in inflammation and acute phase response but similar genotoxicity in mice following pulmonary exposure to graphene oxide and reduced graphene oxide. PLoS One, 12(6), e0178355. doi:10.1371/journal.pone.0178355

Bourdon, J. A., Halappanavar, S., Saber, A. T., Jacobsen, N. R., Williams, A., Wallin, H., . . . Yauk, C. L. (2012). Hepatic and pulmonary toxicogenomic profiles in mice intratracheally instilled with carbon black nanoparticles reveal pulmonary inflammation, acute phase response, and alterations in lipid homeostasis. Toxicol Sci, 127(2), 474-484. doi:10.1093/toxsci/kfs119

Brand, P., Bauer, M., Gube, M., Lenz, K., Reisgen, U., Spiegel-Ciobanu, V. E., & Kraus, T. (2014). Relationship between welding fume concentration and systemic inflammation after controlled exposure of human subjects with welding fumes from metal inert gas brazing of zinc-coated materials. J Occup Environ Med, 56(1), 1-5. doi:10.1097/JOM.0000000000000061

Christophersen, D. V., Moller, P., Thomsen, M. B., Lykkesfeldt, J., Loft, S., Wallin, H., . . . Jacobsen, N. R. (2021). Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE(-/-) mice. FASEB J, 35(3), e21307. doi:10.1096/fj.202002017R

Danielsen, P. H., Bendtsen, K. M., Knudsen, K. B., Poulsen, S. S., Stoeger, T., & Vogel, U. (2021). Nanomaterial- and shape-dependency of TLR2 and TLR4 mediated signaling following pulmonary exposure to carbonaceous nanomaterials in mice. Part Fibre Toxicol, 18(1), 40. doi:10.1186/s12989-021-00432-z

Erdely, A., Liston, A., Salmen-Muniz, R., Hulderman, T., Young, S. H., Zeidler-Erdely, P. C., . . . Simeonova, P. P. (2011). Identification of systemic markers from a pulmonary carbon nanotube exposure. J Occup Environ Med, 53(6 Suppl), S80-86. doi:10.1097/JOM.0b013e31821ad724

Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. N Engl J Med, 340(6), 448-454. doi:10.1056/NEJM199902113400607

Gutierrez, C. T., Loizides, C., Hafez, I., Brostrom, A., Wolff, H., Szarek, J., . . . Vogel, U. (2023). Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. Part Fibre Toxicol, 20(1), 4. doi:10.1186/s12989-023-00514-0

Hadrup, N., Knudsen, K. B., Berthing, T., Wolff, H., Bengtson, S., Kofoed, C., . . . Vogel, U. (2019). Pulmonary effects of nanofibrillated celluloses in mice suggest that carboxylation lowers the inflammatory and acute phase responses. Environ Toxicol Pharmacol, 66, 116-125. doi:10.1016/j.etap.2019.01.003

Hadrup, N., Rahmani, F., Jacobsen, N. R., Saber, A. T., Jackson, P., Bengtson, S., . . . Vogel, U. (2019). Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology, 13(9), 1275-1292. doi:10.1080/17435390.2019.1654004

Hartmann, L., Bauer, M., Bertram, J., Gube, M., Lenz, K., Reisgen, U., . . . Brand, P. (2014). Assessment of the biological effects of welding fumes emitted from metal inert gas welding processes of aluminium and zinc-plated materials in humans. Int J Hyg Environ Health, 217(2-3), 160-168. doi:10.1016/j.ijheh.2013.04.008

Kim, J. Y., Chen, J. C., Boyce, P. D., & Christiani, D. C. (2005). Exposure to welding fumes is associated with acute systemic inflammatory responses. Occup Environ Med, 62(3), 157-163. doi:10.1136/oem.2004.014795

Meier, R., Cascio, W. E., Ghio, A. J., Wild, P., Danuser, B., & Riediker, M. (2014). Associations of short-term particle and noise exposures with markers of cardiovascular and respiratory health among highway maintenance workers. Environ Health Perspect, 122(7), 726-732. doi:10.1289/ehp.1307100

Moldoveanu, B., Otmishi, P., Jani, P., Walker, J., Sarmiento, X., Guardiola, J., . . . Yu, J. (2009). Inflammatory mechanisms in the lung. J Inflamm Res, 2, 1-11. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22096348

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