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Key Event: 1438

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Transcription of genes encoding acute phase proteins, Increased

Short name

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Increased transcription of genes encoding acute phase proteins

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
lung

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
acute-phase response	Acute phase proteins	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

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

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

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

Life Stages

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

Life stage	Evidence
All life stages	High

Sex Applicability

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

Term	Evidence
Male	High
Female	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Acute phase proteins (APPs) are proteins that have an increase in plasma concentration of at least 25% during an acute phase response (Gabay & Kushner, 1999; Mantovani & Garlanda, 2023). 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 (Cray, Zaias, & Altman, 2009; Gabay & Kushner, 1999). All animals--from fish to mammals--have APP, but the type of major APP differs by species (Cray, 2012).

It is widely accepted that APPs are mainly produced in the liver, while several other tissues have been shown to express APPs. In humans, APP genes have been shown to be expressed in the adrenal gland, adipose tissue, appendix, gall bladder, heart, kidney, liver, lung, placenta, prostate, salivary gland, skin, small intestine, stomach, thymus, thyroid, trachea and uterus (de Dios et al., 2018; NCBI, 2023; Schrödl et al., 2016; Urieli-Shoval, Cohen, Eisenberg, & Matzner, 1998; Venteclef, Jakobsson, Steffensen, & Treuter, 2011). In mice, APPs have been shown to be expressed in the adrenal gland, bladder, central nervous system, colon, duodenum, genital fat pad, heart, kidney, large intestine, limbs, liver, lung, mammary gland, ovary, placenta, small intestine, spleen, subcutaneous fat pad, testis and thymus (Kalmovarin et al., 1991; NCBI, 2023; Saber et al., 2013).

Table 1 presents a list of acute phase response genes in humans and mice according the National Center for Biotechnology Information (NCBI): Table 1.

It is important to note that humans and mice express four SAA isoforms (Saa1, Saa2, Saa3 and Saa4), while Saa3 is a pseudogene in humans (Shridas & Tannock, 2019). CRP is expressed in humans and mice, although only moderately expressed in mice (Pepys & Hirschfield, 2003).

In mice, Saa1, Saa2 and Saa3 are all expressed in lung tissue (Saber et al., 2014). Furthermore, 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 Saa isoform expressed in liver tissue after exposure to particles (Halappanavar et al., 2011; Poulsen et al., 2017; Saber et al., 2014).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

No suitable test method was identified in TSAR - Tracking System for Alternative methods towards Regulatory acceptance at https://tsar.jrc.ec.europa.eu/type-regulationstandard/oecd (assessed on May 21, 2026). However, a number of other methods are described in the scientific literature:

Gene expression of acute phase proteins (APPs) can be measured from tissue samples using quantitative Polymerase Chain Reaction (PCR). This technique allows the amplification of selected fragments of DNA or cDNA by using primers (i.e. known end-portions of the selected DNA). By repeated cycles of transcription, DNA is amplified. The use of fluorescent probes to quantify the expression the targeted DNA, as the binding of the probe to this DNA emits a fluorescent signal. Sequences of RNA can be quantify using PCR, by first synthetizing DNA from a RNA sample, resulting in cDNA. This technique is called reverse transcriptase PCR (Nelson, Nelson, Lehninger, & Cox, 2017).

Other techniques for evaluating the expression of several APPs at the same time are microarray analysis, total RNA sequencing or single cell sequencing (Halappanavar et al., 2011; Nelson et al., 2017; Voss et al., 2025).

To evaluate this key event in mice, gene expression of Saa3 can be quantified in lung tissue and Saa1 gene expression in liver tissue after exposure to a stressor (Halappanavar et al., 2011; Poulsen et al., 2017; Saber et al., 2014).

In humans, it is not common to measure gene expression as a tissue sample is required, however gene expression of crp, saa1, saa2 and saa4 can be measured from samples taken during surgery (Calero et al., 2014).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic applicability: Acute phase response is part of the immune response and is observed in vertebrate species (Cray et al., 2009).
Life stage applicability: This key event is applicable to all life stages (Gabay & Kushner, 1999; Hansen et al., 2024; O'Donnell et al., 2009).
Sex applicability: This key event is applicable to male and female sexes (Emerging Risk Factors et al., 2010).

References

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

Calero, C., Arellano, E., Lopez-Villalobos, J. L., Sanchez-Lopez, V., Moreno-Mata, N., & Lopez-Campos, J. L. (2014). 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

Cray, C. (2012). Acute phase proteins in animals. Prog Mol Biol Transl Sci, 105, 113-150. doi:10.1016/B978-0-12-394596-9.00005-6

Cray, C., Zaias, J., & Altman, N. H. (2009). Acute phase response in animals: a review. Comp Med, 59(6), 517-526. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20034426

de Dios, O., Gavela-Perez, T., Aguado-Roncero, P., Perez-Tejerizo, G., Ricote, M., Gonzalez, N., . . . Soriano-Guillen, L. (2018). C-reactive protein expression in adipose tissue of children with acute appendicitis. Pediatr Res, 84(4), 564-567. doi:10.1038/s41390-018-0091-z

Emerging Risk Factors, C., Kaptoge, S., Di Angelantonio, E., Lowe, G., Pepys, M. B., Thompson, S. G., . . . Danesh, J. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet, 375(9709), 132-140. doi:10.1016/S0140-6736(09)61717-7

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

Halappanavar, S., Jackson, P., Williams, A., Jensen, K. A., Hougaard, K. S., Vogel, U., . . . Wallin, H. (2011). 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(6), 425-439. doi:10.1002/em.20639

Hansen, S. S. K., Krautz, R., Rago, D., Havelund, J., Stigliani, A., Faergeman, N. J., . . . Sandelin, A. (2024). Pulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation. Nat Commun, 15(1), 4711. doi:10.1038/s41467-024-48492-x

Kalmovarin, N., Friedrichs, W. E., O'Brien, H. V., Linehan, L. A., Bowman, B. H., & Yang, F. (1991). Extrahepatic expression of plasma protein genes during inflammation. Inflammation, 15(5), 369-379. doi:10.1007/BF00917353

Mantovani, A., & Garlanda, C. (2023). Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med, 388(5), 439-452. doi:10.1056/NEJMra2206346

NCBI. (2023). Retrieved from https://www.ncbi.nlm.nih.gov/gene

Nelson, D. L., Nelson, D. L., Lehninger, A. L., & Cox, M. M. (2017). Lehninger Principles of biochemistry (Seventh edition ed.). Macmillan Higher Education: Basingstoke.

O'Donnell, A., Fowkes, F. J., Allen, S. J., Imrie, H., Alpers, M. P., Weatherall, D. J., & Day, K. P. (2009). The acute phase response in children with mild and severe malaria in Papua New Guinea. Trans R Soc Trop Med Hyg, 103(7), 679-686. doi:10.1016/j.trstmh.2009.03.023

Pepys, M. B., & Hirschfield, G. M. (2003). C-reactive protein: a critical update. J Clin Invest, 111(12), 1805-1812. doi:10.1172/JCI18921

Poulsen, S. S., Knudsen, K. B., Jackson, P., Weydahl, I. E., Saber, A. T., Wallin, H., & Vogel, U. (2017). Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice. PLoS One, 12(4), e0174167. doi:10.1371/journal.pone.0174167

Saber, A. T., Jacobsen, N. R., Jackson, P., Poulsen, S. S., Kyjovska, Z. O., Halappanavar, S., . . . Vogel, U. (2014). Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 6(6), 517-531. doi:10.1002/wnan.1279

Saber, A. T., Lamson, J. S., Jacobsen, N. R., Ravn-Haren, G., Hougaard, K. S., Nyendi, A. N., . . . Vogel, U. (2013). Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk. PLoS One, 8(7), e69020. doi:10.1371/journal.pone.0069020

Schrödl, W., Büchler, R., Wendler, S., Reinhold, P., Muckova, P., Reindl, J., & Rhode, H. (2016). Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine. 10(11), 1077-1092. doi:https://doi.org/10.1002/prca.201600028

Shridas, P., & Tannock, L. R. (2019). Role of serum amyloid A in atherosclerosis. Curr Opin Lipidol, 30(4), 320-325. doi:10.1097/MOL.0000000000000616

Urieli-Shoval, S., Cohen, P., Eisenberg, S., & Matzner, Y. (1998). Widespread expression of serum amyloid A in histologically normal human tissues. Predominant localization to the epithelium. J Histochem Cytochem, 46(12), 1377-1384. doi:10.1177/002215549804601206

Venteclef, N., Jakobsson, T., Steffensen, K. R., & Treuter, E. (2011). Metabolic nuclear receptor signaling and the inflammatory acute phase response. Trends Endocrinol Metab, 22(8), 333-343. doi:10.1016/j.tem.2011.04.004

Voss, C., Han, L., Ansari, M., Strunz, M., Haefner, V., Angelidis, I., . . . Stoeger, T. (2025). Toward a ToxAtlas of Carbon-Based Nanomaterials: Single-Cell RNA Sequencing Reveals Initiating Cell Circuits in Pulmonary Inflammation. ACS Nano, 19(45), 39139-39156. doi:10.1021/acsnano.5c12054