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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	adjacent	High	Moderate	Arthur Author (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 Do not cite	Under Development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 enconding acute phase proteins (Key event 1438) in different tissues, mainly lungs and liver. 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

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 broncheoalveolar 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 (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).

The table in the following link 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): Empirical evidence KER2.

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

The table in the following link 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 viceversa. 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: Inconsistent evidence KER2.

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

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).

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

It has been shown that pro-inflammatory mediators concentrations increase before the expression of genes enconding acute phase proteins:

Upregulation of cytokine genes [Interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor 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).

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

Cray, C., Zaias, J., & Altman, N. H. (2009). Acute phase response in animals: a review. Comp Med, 59(6), 517-526.

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

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

Jackson, P., Hougaard, K. S., Vogel, U., Wu, D., Casavant, L., Williams, A., . . . Halappanavar, S. (2012). Exposure of pregnant mice to carbon black by intratracheal instillation: toxicogenomic effects in dams and offspring. Mutat Res, 745(1-2), 73-83. doi:10.1016/j.mrgentox.2011.09.018

Janeway, C., Murphy, K. P., Travers, P., & Walport, M. (2008). Janeway's immunobiology (7. ed. / Kenneth Murphy, Paul Travers, Mark Walport. ed.). New York, NY: Garland Science.

Jeyaseelan, S., Chu, H. W., Young, S. K., & Worthen, G. S. (2004). Transcriptional profiling of lipopolysaccharide-induced acute lung injury. Infect Immun, 72(12), 7247-7256. doi:10.1128/IAI.72.12.7247-7256.2004

Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., . . . Kohler, G. (1994). Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature, 368(6469), 339-342. doi:10.1038/368339a0

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

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

Ramadori, G., Van Damme, J., Rieder, H., & Meyer zum Buschenfelde, K. H. (1988). Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha. Eur J Immunol, 18(8), 1259-1264. doi:10.1002/eji.1830180817

Uhlar, C. M., & Whitehead, A. S. (1999). Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem, 265(2), 501-523. doi:10.1046/j.1432-1327.1999.00657.x

Van Hoecke, L., Job, E. R., Saelens, X., & Roose, K. (2017). Bronchoalveolar Lavage of Murine Lungs to Analyze Inflammatory Cell Infiltration. J Vis Exp(123). doi:10.3791/55398

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