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Key Event: 1439

Key Event Title

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

Systemic acute phase response

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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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
blood

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 response (APR) is the systemic response to acute and chronic inflammatory states, for example bacterial infection, trauma and infarction. Acute phase proteins (APP) have been shown to be valuable biomarkers as increase can occur with inflammation, infection, neoplasia, stress, and trauma (Cray, 2012). Proteins are considered APP when their plasma concentration changes at least 25% (up or down) in response to these stressors (Gabay & Kushner, 1999). All animals--from fish to mammals--have APP, but the type of major APP differs by species (Cray, 2012).

APPs that increase in concentration during APR are called positive APP, while negative APP are decreased during APR (Gabay & Kushner, 1999). In humans, the two major positive APPs are C-reactive protein (CRP) and serum amyloid A (SAA), whose concentration can increase more than 1000-fold during an acute phase response (Gabay & Kushner, 1999). Additional human acute phase proteins include Alpha-1 antitrypsin, albumin, alpha-2 macroglobulin, ceruloplasmin, fibrinogen, haptoglobin, serum amyloid P, and transferrin (Cray, 2012). In mice, the major positive APPs (i.e. the APPs whose plasma concentration changes the most during APR) are SAA, haptoglobin and serum amyloid P (Cray, Zaias, & Altman, 2009).

APPs are detected in the blood. The organ of biosynthesis of the APPs may vary, and increased mRNA levels of acute phase genes in organ tissue may provide evidence of APP expression in a given organ. Traditionally, the liver has been regarded as a major site of APP biosynthesis (Gabay & Kushner, 1999). However, other organs such as the lung may express APP following exposure to stressors (Saber et al., 2013). In addition, acute phase response is also characterized by fever and leucocytosis (Gabay & Kushner, 1999).

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).

Other methods include:

Systemic acute phase response is assessed by measuring acute phase protein (APP) concentrations in blood, plasma or serum.

In mice, serum amyloid A (SAA) isoforms are measured using enzyme-linked immunosorbent assay (ELISA) assays or Western blot (Christophersen et al., 2021; Gutierrez et al., 2023; Hadrup et al., 2019; Halappanavar et al., 2011; Poulsen et al., 2017). ELISA assays allows the measurement of proteins in a sample by adsorbing the desired proteins (antigens) to an inert surface. Using antibodies specific to the protein and an enzyme that catalyzes the reaction, a colorimetric signal is produced and measured (Nelson, Nelson, Lehninger, & Cox, 2017). In the case of Western blot, also called immunoblot assay, proteins in a sample are first separated by gel electrophoresis. Following, the proteins are transferred to a membrane and treated with antibodies, obtaining a coloured precipitate along the band of the desired protein (Nelson et al., 2017).

In humans, most often C-reactive protein (CRP) and SAA are measured. These proteins are measured by immunoassays detecting single or multiple proteins (Adetona et al., 2017; Andersen et al., 2019; Baumann et al., 2018; Meier et al., 2014; Monse et al., 2018; Walker et al., 2022; Wyatt, Devlin, Rappold, Case, & Diaz-Sanchez, 2020). In addition, CRP is measured by turbidimetric (Barregard et al., 2006; Kim, Chen, Boyce, & Christiani, 2005; Sikkeland et al., 2018) and nephelometric assays (Brand et al., 2014).

For both techniques, a blood sample (serum or plasma) is mixed with a suspension of latex beads coated with CRP antibodies. When CRP binds to the beads, a complex is formed that produces the scattering of light. The amount of light scattered is proportional to the amount of complexes formed. While in nephelometry the amount of light scaterred is measure, in turbidimetry the amount of light that passes through the suspension is measured. The measurements are later converted to CRP concentration using a calibration curve (Drieghe, Alsaadi, Tugirimana, & Delanghe, 2014; Hamilton, 2014).

CRP is used in the clinical setting as a marker of systemic inflammation.

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 vertebrates (Cray et al., 2009).
Life stages applicability: This key event is applicable to all life stages (Gabay & Kushner, 1999; Hansen et al., 2024; Nebbioso et al., 2026; 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

Adetona, A. M., Adetona, O., Gogal, R. M., Jr., Diaz-Sanchez, D., Rathbun, S. L., & Naeher, L. P. (2017). Impact of Work Task-Related Acute Occupational Smoke Exposures on Select Proinflammatory Immune Parameters in Wildland Firefighters. J Occup Environ Med, 59(7), 679-690. doi:10.1097/JOM.0000000000001053

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

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

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

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

Drieghe, S. A., Alsaadi, H., Tugirimana, P. L., & Delanghe, J. R. (2014). A new high-sensitive nephelometric method for assaying serum C-reactive protein based on phosphocholine interaction. Clinical chemistry and laboratory medicine, 52(6), 861-867. doi:10.1515/cclm-2013-0669

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

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., 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

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

Hamilton, R. G. (2014). Methods (In Vitro and In Vivo): Nephelometry and Turbidimetry. In Encyclopedia of Medical Immunology.

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

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

Monse, C., Hagemeyer, O., Raulf, M., Jettkant, B., van Kampen, V., Kendzia, B., . . . Merget, R. (2018). Concentration-dependent systemic response after inhalation of nano-sized zinc oxide particles in human volunteers. Part Fibre Toxicol, 15(1), 8. doi:10.1186/s12989-018-0246-4

Nebbioso, A., Eggermont, I., Vicinanza, A., Le, P. Q., Vitali, N., Auge, G., & Lefevre, N. (2026). Mind the "CRP gender gap"! sex differences in CRP evolution over time in neonatal sepsis: a monocentric retrospective cohort study. Biol Sex Differ, 17(1). doi:10.1186/s13293-026-00841-9

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

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., 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

Sikkeland, L. I. B., Borander, A. K., Voie, O. A., Aass, H. C. D., Ovstebo, R., Aukrust, P., . . . Ueland, T. (2018). Systemic and Airway Inflammation after Exposure to Fumes from Military Small Arms. Am J Respir Crit Care Med, 197(10), 1349-1353. doi:10.1164/rccm.201709-1857LE

Walker, E. S., Fedak, K. M., Good, N., Balmes, J., Brook, R. D., Clark, M. L., . . . Peel, J. L. (2022). 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(3), 565-578. doi:10.1080/09603123.2020.1785402

Wyatt, L. H., Devlin, R. B., Rappold, A. G., Case, M. W., & Diaz-Sanchez, D. (2020). Low levels of fine particulate matter increase vascular damage and reduce pulmonary function in young healthy adults. Part Fibre Toxicol, 17(1), 58. doi:10.1186/s12989-020-00389-5