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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	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 Do not cite	Under Development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 interaction of stressors with the lung resident cell membrane components (Key event 1495) and transcription of genes encoding acute phase proteins (Key event 1438) 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

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 (Key event 1438) is triggered by cellular pattern-recognition molecules, through a cytokine cascade (Mantovani & Garlanda, 2023). In the lungs, this cytokine cascade is produced by epithelial cells and resident macrophages (Key event 1495) (Moldoveanu et al., 2009).

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

Any substance that is inhaled will interact with a component of the respiratory system, including cells. Any study that shows that inhalation exposure leads to transcription of genes encoding acute phase protein is considered evidence for this KER, even if the specific interaction between the substance and the respiratory system has not been investigated.

The following link presents evidence for this KER. Exposure through the respiratory system (inhalation or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components (Key event 1495), while the transcription of genes encoding acute phase proteins was measured in tissues (Key event 1438): Empirical evidence KER5.

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; 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 following link 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: Uncertainties KER5.

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

The interaction of insoluble nanomaterials with the lungs (Key event 1495) (measured in dosed surface area: dosed mass multiply by specific surface area) is correlated to the expression of Saa3 mRNA levels in mice lung tissue (Key event 1438) and the responses show a linear regression, in female C57BL/6J mice 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 Saa3mRNA = 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

After exposure to titanium dioxide nanoparticles in mice, expression of Saa1 mRNA in the liver is short lasting, while expression of Saa3 mRNA in lung tissue is longer lasting, as it has been observed 28 day after exposure (Wallin et al., 2017).

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 as lung, liver and arteries (Meek et al., 1994; Urieli-Shoval et al., 1998).

References

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

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

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

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

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

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

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.

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., 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., 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

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