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Interaction with the lung cell membrane leads to Systemic APR
Key Event Relationship Overview
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||non-adjacent||High||Moderate||Ulla Vogel (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
This KER presents the association between the interaction of stressors with the lungs and the induction of systematic acute phase response. The evidence of the KER presented is based on animal studies (mice), controlled human studies and epidemiological studies.
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility is high. Pulmonary inflammation occurs when stressor interact with the airways 1 and acute phase response is induced during inflammatory conditions 2. It has been shown (see table below) that exposure to different stressors produces an increase of acute phase proteins in blood [i.e. C-reactive protein (CRP) and serum amyloid A (SAA)] in humans and mice.
Uncertainties and Inconsistencies
In the case of nanomaterials, it has been shown that physicochemical characteristics as size, surface area, surface functionalization, shape, composition, among others, affect the magnitude and duration of acute phase response in mice 3-5.
It has been observed that in most controlled human studies, an increase in CRP and/or SAA was observed after exposure to particulate matter 6-10. However, in other human studies the exposure did not induce acute phase response11,12, maybe due to a low level of exposure 13
Known modulating factors
In the case of some insoluble nanomaterials, it has been observed that log-transformed dosed surface area (dosed mass multiply by specific surface area) and log-transformed SAA3 plasma levels in mice presented a Pearson’s correlation coefficient of 0.92 (p <0.001) 1 day post-exposure 4 (Figure 1). The linear regression formula obtained was Log SAA3 = 0.9459 *Log Dosed surface area – 2.854 (p=0.01). The correlation coefficient between log-transformed dosed surface area and log-transformed SAA1/2 plasma levels was 0.83 (p<0.05) and the linear regression formula was Log SAA1/2 = 0.6368 *Log Dosed surface area +0.09524 (p=0.01) 4 (Figure 2).
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) 4.
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) 4.
In mice, increased SAA levels are observed 1 and 3 days after most exposures, however increased SAA levels are not frequently observed 28 or 90 days after exposure 3,14-17.
In humans, increased SAA and CRP has been observed 22h and 2 days after exposure to zinc oxide, but not 3 days after exposure 7. 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 10.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Systemic acute phase response measured as elevation of CRP and SAA in humans, and SAA in mice has been shown after exposure to several stressors (see Empirical evidence).
1 Moldoveanu, B. et al. Inflammatory mechanisms in the lung. J Inflamm Res 2, 1-11 (2009).
2 Gabay, C. & Kushner, I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340, 448-454, doi:10.1056/NEJM199902113400607 (1999).
3 Poulsen, S. S. et al. Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice. PLoS One 12, e0174167, doi:10.1371/journal.pone.0174167 (2017).
4 Gutierrez, C. T. et al. Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. Part Fibre Toxicol 20, 4, doi:10.1186/s12989-023-00514-0 (2023).
5 Bengtson, S. et al. 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, e0178355, doi:10.1371/journal.pone.0178355 (2017).
6 Monse, C. et al. Concentration-dependent systemic response after inhalation of nano-sized zinc oxide particles in human volunteers. Part Fibre Toxicol 15, 8, doi:10.1186/s12989-018-0246-4 (2018).
7 Monse, C. et al. Health effects after inhalation of micro- and nano-sized zinc oxide particles in human volunteers. Arch Toxicol 95, 53-65, doi:10.1007/s00204-020-02923-y (2021).
8 Walker, E. S. et al. Acute differences in blood lipids and inflammatory biomarkers following controlled exposures to cookstove air pollution in the STOVES study. Int J Environ Health Res 32, 565-578, doi:10.1080/09603123.2020.1785402 (2022).
9 Wyatt, L. H., Devlin, R. B., Rappold, A. G., Case, M. W. & Diaz-Sanchez, D. Low levels of fine particulate matter increase vascular damage and reduce pulmonary function in young healthy adults. Part Fibre Toxicol 17, 58, doi:10.1186/s12989-020-00389-5 (2020).
10 Baumann, R. et al. Systemic serum amyloid A as a biomarker for exposure to zinc and/or copper-containing metal fumes. J Expo Sci Environ Epidemiol 28, 84-91, doi:10.1038/jes.2016.86 (2018).
11 Andersen, M. H. G. et al. Association between polycyclic aromatic hydrocarbon exposure and peripheral blood mononuclear cell DNA damage in human volunteers during fire extinction exercises. Mutagenesis 33, 105-115, doi:10.1093/mutage/gex021 (2018).
12 Andersen, M. H. G. et al. 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, 539-548, doi:10.1002/em.22193 (2018).
13 Andersen, M. H. G. et al. Health effects of exposure to diesel exhaust in diesel-powered trains. Part Fibre Toxicol 16, 21, doi:10.1186/s12989-019-0306-4 (2019).
14 Bourdon, J. A. et al. 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, 474-484, doi:10.1093/toxsci/kfs119 (2012).
15 Poulsen, S. S. et al. Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease. Toxicol Appl Pharmacol 283, 210-222, doi:10.1016/j.taap.2015.01.011 (2015).
16 Poulsen, S. S. et al. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol 284, 16-32, doi:10.1016/j.taap.2014.12.011 (2015).
17 Hadrup, N. et al. 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 (2019).