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Relationship: 2958

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

Interaction with the lung cell membrane 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
Interaction with the lung cell membrane
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 non-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 Do not cite Under Development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 interaction of stressors with the lung resident cell membrane components (KE1495) and transcription of genes encoding acute phase proteins (KE1438) in different tissues, mainly lungs and liver. The evidence of the KER presented is based on animal studies (mice).

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 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. After cells sense pathogens, tissue damage or dysmetabolism, production of acute phase proteins (KE 1438) is triggered by cellular pattern-recognition molecules, through a cytokine cascade (Mantovani & Garlanda, 2023). Specifically, IL-6, TNF and IL-1b are known transcriptional inducers of acute phase response gene transcription (Gabay & Kushner, 1999).  In the lungs, the cytokine cascade is produced by epithelial cells and resident macrophages (KE1495) (Moldoveanu et al., 2009).

Thus, pulmonary exposure to diesel engine exhaust in female mice led to increased levels of several cytokines including CCL2, CXCL1, IL-1B and IL-6 24 h post-exposure (Bendtsen et al., 2020; McCarrick et al., 2025). This was accompanied by increased transcription of acute phase response genes in lung tissue (Gliga et al., 2026). Among others, TNF, IL-6 and IL-1B were identified as upstream regulators of pulmonary transcription (Gliga et al., 2026).

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

Although it is suggested that acute phase proteins are mainly produced in the liver (Gabay & Kushner, 1999), it has been shown that in mice, the liver has little upregulation of Saa genes after exposure to ultrafine carbon particles or diesel exhaust particle, while it is in the lung where there is a marked expression of Saa3 mRNA (Saber et al., 2009, 2013).

Although it is suggested that acute phase proteins are mainly produced in the liver (Gabay & Kushner, 1999), it has been shown that in mice, the liver has little upregulation of Saa genes after exposure to ultrafine carbon particles or diesel exhaust particle, while in the lung where there is a marked expression of Saa3 mRNA (Saber et al., 2009; Saber et al., 2013).

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 the expression of acute phase proteins in mice (Barfod et al., 2020; Bengtson et al., 2017; Danielsen et al., 2020; Gutierrez et al., 2023; Hadrup et al., 2019; Poulsen et al., 2017; Wallin et al., 2017).

In humans, measuring gene expression of acute phase proteins is not very common as a tissue sample is needed, while measuring acute phase protein in blood in more common. However, Saa mRNA has been shown expressed in different tissues including lung, liver and arteries (Meek, Urieli-Shoval, & Benditt, 1994; Urieli-Shoval, Cohen, Eisenberg, & Matzner, 1998).

The table below presents inconsistencies for this KER, where substance interaction with lung resident cell membrane components has occurred, while transcription of genes encoding acute phase proteins was not observed. Exposure through the respiratory system (intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components, while the transcription of genes encoding acute phase proteins was measured in tissues.

Species

Stressor

Substance interaction with lung residents cell membrane components

Transcription of genes encoding acute phase proteins

Reference

Mouse

Unmodified halloysites

Yes, intratracheal instillation of 6, 18 and 54 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, intratracheal instillation of 18 and 54 µg.

No change in Saa3 mRNA expression in lung tissue.

(Gutierrez et al., 2023)

Mouse

Cube titanium dioxide

Yes, intratracheal instillation of 18, 54 and 162 µg.

No change in Saa3 mRNA expression in lung tissue. No change in Saa1 mRNA expression in liver tissue.

(Danielsen et al., 2020)

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Dose response relationship between lung exposure and gene expression of acute phase response genes including Saa3 in lung tissue is consistently observed in the studies listed above. For example, following pulmonary exposure to three different particle types (carbon black particles, titanium dioxide particles and carbon nanotubes), dose-dependent transcription of acute phase response genes was observed in lung tissue at day 1, 3 and 28 days post-exposure in female mice (Saber et al., 2014). The dose dependency was observed in two ways; in terms of the number of differentially expressed acute phase response genes and in terms of the fold increase of the most differentially expressed acute phase response gene, Saa3.

In another study, it was demonstrated that the total surface area of the pulmonary deposited insoluble particles  correlated with the expression of Saa3 mRNA levels in lung tissue in female C57BL/6J mice (KE1438) The responses showed a linear regression, 1 day after intratracheal instillation (Gutierrez et al., 2023) (Figure 1). The Pearson’s correlation coefficient was 0.70 (p <0.001) between log-transformed dosed surface area and log-transformed Saa3 mRNA levels in mice lung tissue. The linear regression formula obtained was Log Saa3 mRNA = 1.080*Log Dosed surface area + 0.9415 (p<0.001)(Gutierrez et al., 2023).

Figure 1. Correlations between dosed surface area and Saa3 mRNA levels in lung tissue, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

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

Following pulmonary exposure to three different particle types, dose-dependent transcription of acute phase response genes was observed in lung tissue at day 1, 3 and 28 days post-exposure in female mice (Saber et al., 2014). The dose dependency was observed in two ways; in terms of the number of differentially expressed acute phase response genes and in terms of the fold increase of the most differentially expressed acute phase response gene, Saa3. Thus, pulmonary exposure to particles induced Saa3 mRNA transcription up to 28 days post-exposure. In contrast, the hepatic acute phase response following inhalation or pulmonary instillation of nanoparticles is much smaller than the observed pulmonary acute phase response, or may even be entirely absent. When observed,  the hepatic acute phase response was only observed 1 day post-exposure and not at later time points (Poulsen et al., 2017; Saber et al., 2014).

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

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

The expression of Saa mRNA in lung and liver tissue has been shown in mice after pulmonary exposure to a variety of nanomaterials (see Empirical evidence), and in humans in different tissues such as lung, liver and arteries (Meek et al., 1994; Urieli-Shoval et al., 1998).

In humans, increased serum amyloid A (SAA) levels are observed during acute inflammatory conditions such as infection, as well as chronic inflammatory conditions including autoimmune disorders, obesity, type 2 diabetes, and cardiovascular disease (CVD) (den Hartigh, May, Zhang, Chait, & Blaser, 2023). Thus, acute phase response is observed in both sexes and in all age groups.

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

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

Danielsen, P. H., Bendtsen, K. M., Knudsen, K. B., Poulsen, S. S., Stoeger, T., & Vogel, U. (2021). Nanomaterial- and shape-dependency of TLR2 and TLR4 mediated signaling following pulmonary exposure to carbonaceous nanomaterials in mice. Part Fibre Toxicol, 18(1), 40. doi:10.1186/s12989-021-00432-z

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

den Hartigh, L. J., May, K. S., Zhang, X. S., Chait, A., & Blaser, M. J. (2023). Serum amyloid A and metabolic disease: evidence for a critical role in chronic inflammatory conditions. Front Cardiovasc Med, 10, 1197432. doi:10.3389/fcvm.2023.1197432

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

Erdely, A., Liston, A., Salmen-Muniz, R., Hulderman, T., Young, S. H., Zeidler-Erdely, P. C., . . . Simeonova, P. P. (2011). Identification of systemic markers from a pulmonary carbon nanotube exposure. J Occup Environ Med, 53(6 Suppl), S80-86. doi:10.1097/JOM.0b013e31821ad724

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

Halappanavar, S., Saber, A. T., Decan, N., Jensen, K. A., Wu, D., Jacobsen, N. R., . . . Vogel, U. (2015). Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response. Environ Mol Mutagen, 56(2), 245-264. doi:10.1002/em.21936

Husain, M., Saber, A. T., Guo, C., Jacobsen, N. R., Jensen, K. A., Yauk, C. L., . . . Halappanavar, S. (2013). Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. Toxicol Appl Pharmacol, 269(3), 250-262. doi:10.1016/j.taap.2013.03.018

Kyjovska, Z. O., Jacobsen, N. R., Saber, A. T., Bengtson, S., Jackson, P., Wallin, H., & Vogel, U. (2015). DNA strand breaks, acute phase response and inflammation following pulmonary exposure by instillation to the diesel exhaust particle NIST1650b in mice. Mutagenesis, 30(4), 499-507. doi:10.1093/mutage/gev009

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

McCarrick, S., Malmborg, V., Gren, L., Danielsen, P. H., Tuner, M., Palmberg, L., . . . Gliga, A. R. (2025). Pulmonary exposure to renewable diesel exhaust particles alters protein expression and toxicity profiles in bronchoalveolar lavage fluid and plasma of mice. Arch Toxicol, 99(2), 797-814. doi:10.1007/s00204-024-03915-y

Meek, R. L., Urieli-Shoval, S., & Benditt, E. P. (1994). Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function. Proc Natl Acad Sci U S A, 91(8), 3186-3190. doi:10.1073/pnas.91.8.3186

Moldoveanu, B., Otmishi, P., Jani, P., Walker, J., Sarmiento, X., Guardiola, J., . . . Yu, J. (2009). Inflammatory mechanisms in the lung. J Inflamm Res, 2, 1-11. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22096348

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218724/pdf/jir-2-001.pdf

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

Poulsen, S. S., Saber, A. T., Mortensen, A., Szarek, J., Wu, D., Williams, A., . . . Vogel, U. (2015). 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(3), 210-222. doi:10.1016/j.taap.2015.01.011

Poulsen, S. S., Saber, A. T., Williams, A., Andersen, O., Kobler, C., Atluri, R., . . . Vogel, U. (2015). 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(1), 16-32. doi:10.1016/j.taap.2014.12.011

Saber, A. T., Halappanavar, S., Folkmann, J. K., Bornholdt, J., Boisen, A. M., Moller, P., . . . Wallin, H. (2009). Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation. Part Fibre Toxicol, 6, 12. doi:10.1186/1743-8977-6-12

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

Saber, A. T., Mortensen, A., Szarek, J., Koponen, I. K., Levin, M., Jacobsen, N. R., . . . Wallin, H. (2016). Epoxy composite dusts with and without carbon nanotubes cause similar pulmonary responses, but differences in liver histology in mice following pulmonary deposition. Part Fibre Toxicol, 13(1), 37. doi:10.1186/s12989-016-0148-2

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

Wallin, H., Kyjovska, Z. O., Poulsen, S. S., Jacobsen, N. R., Saber, A. T., Bengtson, S., . . . Vogel, U. (2017). Surface modification does not influence the genotoxic and inflammatory effects of TiO2 nanoparticles after pulmonary exposure by instillation in mice. Mutagenesis, 32(1), 47-57. doi:10.1093/mutage/gew046