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Key Event Title
Transcription of genes encoding acute phase proteins, Increased
|Level of Biological Organization|
Key Event Components
|acute-phase response||Acute phase proteins||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Interaction with lung cells leading to atherosclerosis||KeyEvent||Ulla Vogel (send email)||Under development: Not open for comment. Do not cite||Under Development|
|All life stages||High|
Key Event Description
Acute phase response is characterized by the change in plasma concentration of acute phase proteins (APP), along with other physiological changes during inflammatory conditions 1,2. In humans, the major APPs are C-reactive protein and serum amyloid A, while in mice the major APPs are serum amyloid A, haptoglobin and serum amyloid P 1,3.
It is widely accepted than APPs are mainly produced by the liver, however several other tissues have been showed to express APPs; these include lungs, intestines, kidneys, skin and adipose tissue in humans 4-7, and kidney, spleen, brain, lung and testis in mice 8,9. According to National Center for Biotechnology Information (NCBI) serum amyloid A isoforms and C-reactive protein genes in mice have been shown to be expressed in tissue from adrenal gland, bladder, central nervous system, colon, duodenum, genital fat pad, heart, kidney, large intestine, limbs, liver, lung, mammary gland, ovary, placenta, small intestine, subcutaneous fat pad, testis and thymus10. In the case of humans, these genes have been shown to be expressed in tissue from adrenal gland, appendix, fat, gall bladder, heart, kidney, liver, lung, placenta, prostate, salivary gland, small intestine, stomach, thymus, thyroid, trachea and uterus10.
How It Is Measured or Detected
Gene expression of APPs can be measured from tissue samples using quantitative Polymerase Chain Reaction (PCR). Humans and mice express four SAA isoforms (Saa1, Saa2, Saa3 and Saa4), however Saa3 is a pseudogene in humans11. CRP is expressed in humans and mice, although only moderately expressed in mice12.
It has been shown that in mice the Saa3 isoform is the most differentially expressed APP gene in lung tissue and it is not highly expressed in the liver, while Saa1 gene is the most differentially expressed in liver tissue after exposure to particles 13-15. In humans, it has been shown that crp, saa1, saa2 and saa4 gene expression can be measured in lung samples taken during surgery 16. In addition, microarray analysis can be used to evaluate the gene expression of several APPs at the same time 13.
Domain of Applicability
- Taxonomic applicability: APR is part of the immune reponse and is obseved in vertebrate species3.
- Life stage applicability: This key event is applicable to all life stages.
- Sex applicability: This key event is applicable to male and female sexes.
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2 Mantovani, A. & Garlanda, C. Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med 388, 439-452, doi:10.1056/NEJMra2206346 (2023).
3 Cray, C., Zaias, J. & Altman, N. H. Acute phase response in animals: a review. Comp Med 59, 517-526 (2009).
4 Schrödl, W. et al. Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine. 10, 1077-1092, doi:https://doi.org/10.1002/prca.201600028 (2016).
5 de Dios, O. et al. C-reactive protein expression in adipose tissue of children with acute appendicitis. Pediatr Res 84, 564-567, doi:10.1038/s41390-018-0091-z (2018).
6 Urieli-Shoval, S., Cohen, P., Eisenberg, S. & Matzner, Y. Widespread expression of serum amyloid A in histologically normal human tissues. Predominant localization to the epithelium. J Histochem Cytochem 46, 1377-1384, doi:10.1177/002215549804601206 (1998).
7 Venteclef, N., Jakobsson, T., Steffensen, K. R. & Treuter, E. Metabolic nuclear receptor signaling and the inflammatory acute phase response. Trends Endocrinol Metab 22, 333-343, doi:10.1016/j.tem.2011.04.004 (2011).
8 Kalmovarin, N. et al. Extrahepatic expression of plasma protein genes during inflammation. Inflammation 15, 369-379, doi:10.1007/BF00917353 (1991).
9 Saber, A. T. et al. Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk. PLoS One 8, e69020, doi:10.1371/journal.pone.0069020 (2013).
10 NCBI. <https://www.ncbi.nlm.nih.gov/gene> (2023).
11 Shridas, P. & Tannock, L. R. Role of serum amyloid A in atherosclerosis. Curr Opin Lipidol 30, 320-325, doi:10.1097/MOL.0000000000000616 (2019).
12 Pepys, M. B. & Hirschfield, G. M. C-reactive protein: a critical update. J Clin Invest 111, 1805-1812, doi:10.1172/JCI18921 (2003).
13 Halappanavar, S. et al. Pulmonary response to surface-coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in microRNAs: a toxicogenomic study. Environ Mol Mutagen 52, 425-439, doi:10.1002/em.20639 (2011).
14 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).
15 Saber, A. T. et al. Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6, 517-531, doi:10.1002/wnan.1279 (2014).
16 Calero, C. et al. Differential expression of C-reactive protein and serum amyloid A in different cell types in the lung tissue of chronic obstructive pulmonary disease patients. BMC Pulm Med 14, 95, doi:10.1186/1471-2466-14-95 (2014).