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Relationship: 3052

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 Systemic acute phase response

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
Systemic acute phase response

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 non-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 Do not cite Under Development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 the induction of systemic acute phase response (Key event 1439). The evidence of the KER presented is based on animal studies (mice), controlled human studies and epidemiological 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. The production of acute phase proteins during acute phase response is induced by the release of pro-inflammatory markers as interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNF-α) at inflammatory sites (Gabay & Kushner, 1999; Mantovani & Garlanda, 2023).

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).

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

Wyatt et al. observed a decrease in blood neutrophil numbers in humans after exposure to ambient particulate matter although an increase in serum amyloid A (SAA) and C-reactive protein (CRP) was observed. It was mentioned this might be due to the translocation of neutrophil from major vessels to smaller arteries (Wyatt, Devlin, Rappold, Case, & Diaz-Sanchez, 2020).

In the study by Meier et al., the authors obtained a negative association between particulate matter with a diameter of less than 2.5 μm (PM2.5) exposure and blood levels of tumor necrosis factor (TNF-α) and interleukin (IL)-6, while SAA and CRP were positive associated with the exposure. The authors mentioned these results might be due the time point where the samples were taken (Meier et al., 2014).

Barregard et al. also observed that IL-6 levels were lower after exposure to wood smoke than after exposure to clean air. They suggested that this response was due to a possible sequestering of cytokines in the pulmonary capillary bed (Barregard et al., 2006).

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 blood or bronchoalveolar lavage fluid (BALF), while systemic acute phase response was measured as the concentration of acute phase in blood plasma or serum: Uncertainties KER8.

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

Neutrophil number in brochoalveolar lavage fluid (BALF) (indirect measure of the secretion of proinflammatory mediators – Key event 1496) correlates with plasma SAA3 levels (Key event 1439), in female C57BL/6J mice 1 day after intratracheal instillation of metal oxide nanomaterials (Figure 1). The Pearson’s correlation coefficient was 0.79 (p<0.001) between log-transformed neutrophil number in BALF and log-transformed SAA3 plasma protein levels (Gutierrez et al., 2023).

Figure 1. Correlation between neutrophil numbers and SAA3 plasma protein levels in mice 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

A linear dose-response has also been found between neutrophil numbers in BALF and SAA3 plasma protein levels in mice, 1 day after exposure to multiwalled carbon nanotubes (Figure 2) (Poulsen et al., 2017).

Figure 2. Transformed SAA3 protein vs. transformed neutrophil influx. Reproduced from Poulsen et al. (2017).

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 the concentration of pro-inflammatory mediators increases before acute phase proteins:

  • In patients with atherosclerotic renal stenosis, blood interleukin (IL)-6 increased in the first hour after renal artery stenting and reached its highest concentration at 6h, while C-reactive protein (CRP) increased 6h after the treatment, peaking at 24h after treatment (Li et al., 2004).
  • In human infants undergoing cardiopulmonary bypass, it has been observed that blood concentrations of IL-6 significantly increased after cessation of the procedure and remained elevated 24h later, while CRP started increased 6h after bypass and kept increasing at 12h and 24h after bypass (Allan et al., 2010).
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

Interleukin (IL)-1, IL-6 and TNF- α can decrease acute phase response by decreasing their own production through the induction of corticosteroids (Uhlar & Whitehead, 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 conserved in vertebrate species (Cray, Zaias, & Altman, 2009).

References

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

Allan, C. K., Newburger, J. W., McGrath, E., Elder, J., Psoinos, C., Laussen, P. C., . . . McGowan, F. X., Jr. (2010). The relationship between inflammatory activation and clinical outcome after infant cardiopulmonary bypass. Anesth Analg, 111(5), 1244-1251. doi:10.1213/ANE.0b013e3181f333aa

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

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

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.

Li, J. J., Fang, C. H., Jiang, H., Huang, C. X., Hui, R. T., & Chen, M. Z. (2004). Time course of inflammatory response after renal artery stenting in patients with atherosclerotic renal stenosis. Clin Chim Acta, 350(1-2), 115-121. doi:10.1016/j.cccn.2004.07.013

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

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

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

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

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