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Relationship: 2053

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

Increased proinflammatory mediators leads to Increased transcription of genes encoding acute phase proteins

Upstream event

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

Increased proinflammatory mediators

Downstream event

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

Increased transcription of genes encoding acute phase proteins

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	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 Do not cite	Under Development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 secretion of pro-inflammatory mediators (Key event 1496) and transcription of genes encoding acute phase proteins (f. ex. Saa1, Saa2 and Saa3) (Key event 1438) in different tissues, mainly lung and liver. Pro-inflammatory mediators are the secondary messengers that initiate and regulate inflammatory reactions. They are secreted during inflammation in all species. Acute phase proteins are proteins that have an increase in plasma concentration of at least 25% during an acute phase response (Gabay & Kushner, 1999). Acute phase proteins are induced by pro-inflammatory mediators (f. ex. IL-6, TNF-α and IL-1β) and their genes are expressed mainly in the liver, but also in several other tissues (Gabay & Kushner, 1999; Urieli-Shoval et al., 1998). The evidence of the KER presented is based on in vitro studies, animal studies (mice) and human 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 primarily 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. It is known that acute phase proteins are induced by pro-inflammatory cytokines, primary interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNF-α). These cytokines are produced at sites of inflammation, mainly by monocytes and macrophages (Gabay & Kushner, 1999; Mantovani & Garlanda, 2023; Uhlar & Whitehead, 1999; Venteclef, Jakobsson, Steffensen, & Treuter, 2011). Following cytokine release, signaling cascades and transcription factors are activated, regulating the expression of acute phase reaction genes (Venteclef et al., 2011).

In this KER, pulmonary inflammation has been considered as an indirect marker of the release of pro-inflammatory factors because the release of inflammatory mediators (i.e. cytokines and chemokines) recruits immune cells to inflammation sites (Janeway, Murphy, Travers, & Walport, 2008). In mice, pulmonary inflammation is commonly assessed as the number or fraction of neutrophils in the bronchoalveolar lavage fluid (BALF) (Van Hoecke, Job, Saelens, & Roose, 2017).

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

Interleukin (IL)-1 (IL-1α and IL-1β, 10 ng/mL each) and IL-6 (500 units/mL), both in presence of 1 µM dexamethasone, increased the relative levels of serum amyloid A (SAA) mRNA in cultured human adult aortic smooth muscle cells after 20 h (Meek, Urieli-Shoval, & Benditt, 1994).
Human hepatoma cells exposed to IL-6, IL-1β and tumor necrosis factor α (TNF-α) for 20 h showed a reduced synthesis of albumin and increased synthesis of the acute phase proteins C3 and ceruloplasmin. In addition, mice exposed to IL-1β and TNF-α showed an increase of Saa mRNA in liver tissue (Ramadori, Van Damme, Rieder, & Meyer zum Buschenfelde, 1988).
After pulmonary exposure to lipopolysaccharide (LPS) (300 µg/mL), lung tissue from female C57BL/6 mice showed upregulation of several cytokines and chemokines genes and upregulation of the acute phase proteins genes Saa and α₁-protease inhibitor (Jeyaseelan, Chu, Young, & Worthen, 2004).
Mice presenting IL-6 gene disruption (IL-6^-/-) shown a reduced response in liver mRNA levels of acute phase proteins haptoglobin, α1-acid glycoprotein and SAA, after challenged by turpentine, LPS and bacterial infection (Kopf et al., 1994).
After repeated instillation of carbon black nanoparticles, female C57BL/6BomTac mice showed increased expression of chemokine genes along with increased Saa3 gene expression in lung tissue. In addition, dose-response relationships with several cytokine proteins were identified in lung tissue (Jackson et al., 2012).
Intratracheal instillation of titanium dioxide in female C57BL/6 mice showed that 28 days after exposure, several genes of cytokines, chemokines and acute phase proteins were upregulated. Additionally, there were significant increases in inflammatory mediators in lung tissue (Husain et al., 2013).
Intratracheal instillation of diesel exhaust particles and carbon black nanoparticles in female C57BL/6 mice resulted in increased levels of proinflammatory cytokines including IL-6 and IL-1B in the bronchoalveolar lavage fluid, as well as mRNA levels of the genes in lung tissue and increased expression of acute phase genes including Saa3 and Saa1 in lung tissue 24 h post-exposure (Bendtsen et al., 2020; Gliga et al., 2026; McCarrick et al., 2025).
Both protein levels of pro-inflammatory cytokines and mRNA levels of the corresponding genes correlate closely with neutrophil influx following lung exposure to for example diesel engine exhaust particles in mice (Bendtsen et al., 2020; Gliga et al., 2026; McCarrick et al., 2025).

The table below presents evidence of the KER using neutrophil numbers in broncheoalveolar lavage fluid (BALF) as indirect evidence of the release of pro-inflammatory mediators (Key event 1496), while the transcription of genes encoding acute phase proteins was measured in tissues (Key event 1438).

Species	Stressor	Secretion of pro-inflammatory mediators	Transcription of genes encoding acute phase proteins	Reference
Mouse	Ultrafine carbon particles	No significant increase in polymorphonuclear cells (includes neutrophils) in BALF.	Yes, increased Saa3 gene expression at 24 h.	(Andre et al., 2006)
Mouse	Diesel exhaust particles	Yes, significant increase of neutrophils in BALF.	Yes, increased expression of Saa3 genes in lung tissue. No expression of Sap, Saa1 or Saa3 genes on liver tissue.	(Saber et al., 2005, 2009, 2013)
Mouse	Titanium dioxide nanoparticles	Yes, significant increased numbers of neutrophils in BALF.	Yes, increased expression of Saa1 and Saa3 genes in lung tissue	(Halappanavar et al., 2011; Hougaard et al., 2010)
Mouse	Carbon black nanoparticles	Yes, significant increase of neutrophil number 1, 3 and 28 days after exposure.	Yes, significant Saa1, Saa2 and Saa3 gene expression increase in lung tissue, at days 1, 3 and 28 after exposure. Saa3 gene expression increase in liver tissue at day 1 after exposure.	(Bourdon, Halappanavar, et al., 2012; Bourdon, Saber, et al., 2012)
Mouse	Titanium dioxide nanoparticles	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 µg, and 1, 3 and 28 days after exposure to 162 µg.	Yes, increased mRNA expression of Saa3 in lung issue at days 1, 3 and 28 after exposure with 162 µg, and at day 3 with 54 µg.	(Saber et al., 2012, 2013)
Mouse	Carbon black nanoparticles	Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 54 and 162 µg, and 1 and 3 days after exposure to 18 µg.	Yes, increased mRNA expression of Saa3 in lung issue at days 1, 3 and 28 after exposure with 54 µg and 162 µg, and at days 1 and 3 with 18 µg.	(Saber et al., 2012, 2013)
Mouse	Diesel exhaust particles	Yes, increased neutrophil numbers in BALF 3 days after exposure to 54 µg, and 1 and 3 days after exposure to 162 µg.	Yes, increased Saa3 gene expression after 1, 3 and 28 days with 162 µg, at day 28 with 54 µg, and at day 3 with 18 µg.	(Kyjovska et al., 2015)
Mouse	Multiwalled carbon nanotubes (referred as CNT_small)	Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 18, 54 and 162 μg.	Yes, increased differential expression of acute phase response genes in lung and liver tissue.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Multiwalled carbon nanotubes (referred as CNT_large)	Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 18, 54 and 162 μg.	Yes, increased differential expression of acute phase response genes in lung and liver tissue.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Sanding dust from epoxy composite containing carbon nanotubes	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54, 162 and 486 μg, and 28 days after exposure to 486 μg.	Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 486 μg).	(Saber et al., 2016)
Mouse	Sanding dust from epoxy composite without carbon nanotubes	Yes, increased neutrophil numbers in BALF 1 day after exposure to 54, 162 and 486 μg, 3 days after exposure to 162 and 486 μg, and 28 days after exposure to 486 μg.	Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 486 μg).	(Saber et al., 2016)
Mouse	Carbon nanotubes	Yes, increased neutrophil numbers in BALF 1, 3 and 28 after exposure to 18, 54 and 162 μg.	Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 162 μg).	(Saber et al., 2016)
Mouse	Graphene oxide	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg.	Yes, increased mRNA expression of Saa3 in lung tissue, at all dose 1 and 3 days after exposure. Increased gene expression of Saa1 in liver tissue 1 day after exposure to 18 µg, and 3 days after exposure to 162 µg.	(Bengtson et al., 2017)
Mouse	Reduced graphene oxide	Yes, increased neutrophil numbers 1 and 3 days after exposure to 162, and 90 days after exposure to 18, 54 and 162 μg.	Yes, increased mRNA expression of Saa3 in lung tissue, 3 days after exposure to 162 µg. No changes in gene expression of Saa1 in liver tissue.	(Bengtson et al., 2017)
Mouse	Carbon black	Yes, increased neutrophil numbers in BALF 1, 3, 28 and 90 days after exposure.	Yes, increased mRNA expression of Saa3 in lung tissue 1, 3, 28 and 90 days after exposure. Increased gene expression of Saa1 in liver tissue 1 day after exposure.	(Bengtson et al., 2017)
Mouse	Unmodified rutile (TiO₂)	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 and 162 μg, and 28 days after exposure to 162 μ.	Yes, increased expression of Saa3 mRNA in lung tissue 1, 3 and 28 days after exposure to 162 µg. Increased expression of Saa1 in liver tissue 1 day after exposure to 162 µg and 3 days after exposure to 54 and 162 µg.	(Wallin et al., 2017)
Mouse	Surface modified rutile (TiO₂)	Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 54 and 162 μg.	Yes, increased expression of Saa3 mRNA in lung tissue 1, and 28 days after exposure to 54 µg, and 1, 3 and 28 days after exposure to 162 µg. Increased expression of Saa1 in liver tissue 1 day after exposure to 162 µg.	(Wallin et al., 2017)
Mouse	Particulate matter from non-commercial airfield	Yes, increased neutrophil numbers in BALF 1 day after exposure to 18 and 54 µg.	Yes, increased expression of Saa3 mRNA in lung tissue and Saa1 mRNA in liver tissue after 1 day of exposure to 54 µg. No effect after 28 and 90 days.	(Bendtsen et al., 2019)
Mouse	Particulate matter from commercial airport	Yes, increased neutrophil numbers in BALF 1 day after exposure to 18 and 54 µg.	Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 18 and 54 µg. No effect after 28 and 90 days.	(Bendtsen et al., 2019)
Mouse	Diesel exhaust particles	Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 and 162 µg, and 28 days after exposure to 162 μg.	Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 54 and 162 µg, and increased expression of Saa1 mRNA in liver tissue 1 day after exposure to 162 µg. No effect after 28 days.	(Bendtsen et al., 2019)
Mouse	Carbon black	Yes, increased neutrophil in BALF after 1, 28 and 90 days of exposure.	Yes, increased expression of Saa3 mRNA in lung tissue at day 1 and day 90.	(Bendtsen et al., 2019)
Mouse	Coated zinc oxide nanoparticles	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 2 µg, and 28 days after exposure to 0.2 and 0.7 µg.	Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 0.7 and 2 µg. No effect 3 and 28 days after exposure.	(Hadrup et al., 2019)
Mouse	Surface modified halloysites	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 μg, and 28 days after exposure to 6 and 54 μg.	Yes, increase Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to 54 µg. No effect on Saa1 mRNA expression on liver tissue.	(Barfod et al., 2020)
Mouse	Carbon black	Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 162 μg.	Yes, increase Saa3 mRNA expression in lung tissue 1, 3 and 28 days after exposure. No effect on Saa1 mRNA expression on liver tissue.	(Barfod et al., 2020)
Mouse	Nanofil9 (Organomodified nanoclay)	Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 µg, and 3 days after exposure to 18 and 54 µg.	Yes, increased Saa3 mRNA expression in lung tissue 1 day after exposure to all doses, and 3 days after exposure to 6 and 18 µg.	(Di Ianni et al., 2020)
Mouse	NanofilSE3000 (Organomodified nanoclay)	Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 and 162 µg, and 3 days after exposure to 162 µg.	Yes, increased Saa3 mRNA expression in lung tissue 1 day after exposure to 54 and 162 µg, and 3 days after exposure to 54 µg.	(Di Ianni et al., 2020)
Mouse	Bentonite	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg.	Yes, increased Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to all doses, and 28 days after exposure to 162 µg.	(Di Ianni et al., 2020)
Mouse	Carbon black	Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg, and 28 day after exposure to 162 µg.	Yes, increased Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to all doses, and 28 days after exposure to 54 and 162 µg.	(Di Ianni et al., 2020)

Additional evidence can be found in the following link: Additional evidence KER 2053_1 and Additional evidence KER 2053_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

Many in animal studies do not include quantification of protein levels of pro-inflammatory cytokines. Instead, other indicators of an inflammatory response are used. Following pulmonary exposure to particles, neutrophil influx into bronchoalveolar lavage fluid may be used as a proxy for a proinflammatory response. However, as a proxy, neutrophil influx is an imperfect indicator of increased secretion of proinflammatory cytokines. The table below presents inconsistencies for this KER, where secretion of pro-inflammatory mediators has been observed after exposure to a stressor, while systemic acute phase response was not observed, or vice-versa. Secretion of pro-inflammatory mediators was measured as change in concentration of pro-inflammatory markers in blood or increase neutrophil numbers in bronchoalveolar lavage fluid (BALF), while the transcription of genes encoding acute phase proteins was measured in tissues.

Species	Stressor	Secretion of pro-inflammatory mediators	Transcription of genes encoding acute phase proteins	Reference
Mouse	Carbon black	No significant increase of neutrophils in BALF.	Yes, increased expression of Saa3 gene in lung tissue. No expression of Sap, Saa1 or Saa3 genes on liver tissue.	(Saber et al., 2005, 2009, 2013)
Mouse	Uncoated zinc oxide nanoparticles	No increase of neutrophil numbers in BALF after exposure.	Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 2 µg. No effect 3 and 28 days after exposure.	(Hadrup et al., 2019)
Mouse	Unmodified hallosytes	Yes, increased neutrophil numbers in BALF 28 days after exposure to 18 μg.	No effect on Saa3 mRNA expression in lung tissue nor Saa1 mRNA expression in liver tissue.	(Barfod et al., 2020)
Mouse	Aluminum oxide	Yes, increased neutrophil numbers in BALF 1 and 28 days after exposure to 54 µg.	No change in Saa3 mRNA expression in lung tissue.	(Gutierrez et al., 2023)

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Solubility of particles	ZnO and CuO are highly soluble in the low pH of lysozomes. The half-life of ZnO and CuO particles is ca 20 min.	This result in a transient acute phase response, which is no longer present 3 days post-exposure	(Gutierrez et al., 2023; Monse et al., 2018)
Deposited surface area of pulmonary deposited particles	Particle-induced pro-inflammatory response and acute phase response is determined by the total surface area of pulmonary deposited particle	Dose-dependent transcription of acute phase response genes (including Saa3) with an apparent threshold effect	(Barfod et al., 2020; Danielsen et al., 2020; Di Ianni et al., 2022)

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

Neutrophil number in brochoalveolar lavage fluid (indirect measure of the secretion of proinflammatory mediators (Key event 1496) correlates with the expression of Saa3 mRNA levels in lung tissue (Key event 1438), in female C57BL/6J mice 1 and 28 days after intratracheal instillation of metal oxide nanomaterials (Figure 1). The Pearson’s correlation coefficient was 0.82 (p<0.001) between log-transformed neutrophil numbers in brochoalveolar lavage fluid and log-transformed Saa3 mRNA levels in lung tissue (Gutierrez et al., 2023).

Figure 1. Correlations between neutrophil numbers and Saa3 mRNA levels in lung tissue, including data from 1 and 28 days after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

Similarly, close correlation between neutrophil influx and Saa3 mRNA levels in lung tissue was observed following inhalation or instillation exposure to carbon black particles, carbon nanotubes, diesel engine exhaust and titanium dioxide particles (Saber et al., 2013).

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

There is evidence that the time scale is hours to days. Thus, it has been shown that pro-inflammatory mediators concentrations increase before the expression of genes encoding acute phase proteins:

In vitro, Interleukin (IL)-1 (IL-1α and IL-1β, 10 ng/mL each) and IL-6 (500 units/mL), both in presence of 1 µM dexamethasone, increased the relative levels of serum amyloid A (SAA) mRNA in cultured human adult aortic smooth muscle cells after 20 h (Meek et al., 1994)
Upregulation of cytokine genes [Interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor (TNF)- α] was shown to peak around 2h after pulmonary exposure to lipopolysaccharide in female C57BL/6J mice, while upregulation serum amyloid A genes showed their highest upregulation at 8-12h after exposure (Jeyaseelan et al., 2004).
Following pulmonary exposure to insoluble particles and fibers, increased neutrophil cell numbers (as marker of a proinflammatory response) and increased mRNA levels of Saa3 have been observed 1, 3 and 28 h post-exposure, suggesting that the acute phase response may last as long as 28 days (Saber et al., 2013).

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

Some acute phase proteins (f. ex. C-reactive protein, serum amyloid A and complement components) have pro-inflammatory functions, including induction of inflammatory cytokines, chemotaxis and activation of immune cells. On the other hand, other acute phase proteins present anti-inflammatory functions (f. ex. Haptoglobin and fibrinogen) as antioxidative and tissue repair inducer (Gabay & Kushner, 1999).

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

Acute phase response is present in vertebrate species (Cray, Zaias, & Altman, 2009). In addition, serum amyloid A, one of the major acute phase proteins, has been conserved in mammals throughout evolution and has been described in humans, mice, dogs, horses, among others (Uhlar & Whitehead, 1999).

References

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

Andre, E., Stoeger, T., Takenaka, S., Bahnweg, M., Ritter, B., Karg, E., . . . Wjst, M. (2006). Inhalation of ultrafine carbon particles triggers biphasic pro-inflammatory response in the mouse lung. Eur Respir J, 28(2), 275-285. doi:10.1183/09031936.06.00071205

Barfod, K. K., Bendtsen, K. M., Berthing, T., Koivisto, A. J., Poulsen, S. S., Segal, E., . . . Vogel, U. (2020). Increased surface area of halloysite nanotubes due to surface modification predicts lung inflammation and acute phase response after pulmonary exposure in mice. Environ Toxicol Pharmacol, 73, 103266. doi:10.1016/j.etap.2019.103266

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

Bendtsen, K. M., Gren, L., Malmborg, V. B., Shukla, P. C., Tunér, M., Essig, Y. J., . . . Vogel, U. B. (2020). Particle characterization and toxicity in C57BL/6 mice following instillation of five different diesel exhaust particles designed to differ in physicochemical properties. Part Fibre Toxicol, 17(1), 38. doi:10.1186/s12989-020-00369-9

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

Bourdon, J. A., Saber, A. T., Jacobsen, N. R., Jensen, K. A., Madsen, A. M., Lamson, J. S., . . . Vogel, U. B. (2012). Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver. Part Fibre Toxicol, 9, 5. doi:10.1186/1743-8977-9-5

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

Danielsen, P. H., Knudsen, K. B., Strancar, J., Umek, P., Koklic, T., Garvas, M., . . . Vogel, U. (2020). Effects of physicochemical properties of TiO(2) nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice. Toxicol Appl Pharmacol, 386, 114830. doi:10.1016/j.taap.2019.114830

Di Ianni, E., Moller, P., Cholakova, T., Wolff, H., Jacobsen, N. R., & Vogel, U. (2022). Assessment of primary and inflammation-driven genotoxicity of carbon black nanoparticles in vitro and in vivo. Nanotoxicology, 16(4), 526-546. doi:10.1080/17435390.2022.2106906

Di Ianni, E., Moller, P., Mortensen, A., Szarek, J., Clausen, P. A., Saber, A. T., . . . Jacobsen, N. R. (2020). Organomodified nanoclays induce less inflammation, acute phase response, and genotoxicity than pristine nanoclays in mice lungs. Nanotoxicology, 14(7), 869-892. doi:10.1080/17435390.2020.1771786

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

Gliga, A. R., McCarrick, S., Malmborg, V., Kohonen, P., Snigireva, A., Mills, B., . . . Vogel, U. (2026). Similar global transcription patterns in mouse lung tissue following pulmonary exposure to renewable and conventional diesel engine exhaust particles. Environ Toxicol Pharmacol, 122, 104918. doi:10.1016/j.etap.2025.104918

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

Hougaard, K. S., Jackson, P., Jensen, K. A., Sloth, J. J., Loschner, K., Larsen, E. H., . . . Vogel, U. (2010). Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre Toxicol, 7, 16. doi:10.1186/1743-8977-7-16

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