This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1708

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 extracellular matrix deposition leads to Pulmonary fibrosis

Upstream event

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

Increased extracellular matrix deposition

Downstream event

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

Pulmonary fibrosis

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

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
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	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

Fibrosis by definition is the end result of a healing process. It involves a series of lung remodelling and reorganisation events leading to permanent alteration in the lung architecture and a fixed scar tissue or fibrotic lesion (Wallace WA, 2007). Excessive deposition of ECM or collagen is the hallmark of this disease and there is ample evidence to support this KER (Fukuda 1985, Meyer 2017, Richeldi 2017, Thannickal 2004, Zisman 2005).

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

By definition, pulmonary fibrosis is characterized by excessive deposition of extracellular matrix and destruction of native lung architecture (Fukuda 1985, Richeldi 2017, Thannickal 2004). Thus, the plausibility of this association is undisputed.

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

Excessive ECM deposition is the defining characteristic of pulmonary fibrosis, and the evidence to support this relationship is unequivocal. (Meyer 2017, Thannickal 2004, Zisman 2005).

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

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

Since the adverse outcome of lung fibrosis involves multiple cell types, cell - cell interactions and cell–biomolecule interactions, it is difficult to recapitulate the entire process in one model. Therefore, an integrated approach, such as one consisting of cell systems that assess individual KEs and quantitative relationships between the KEs, is needed to predict the AO in humans.

Response-response Relationship

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

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

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

Humans (Zisman 2005, Meyer 2017), rats (Williamson 2015), mice (Williamson 2015).

References

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

Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG. Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol. 1985;118(3):452–475.
Meyer K. C. (2017). Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert review of respiratory medicine, 11(5), 343–359. https://doi.org/10.1080/17476348.2017.1312346
Richeldi, L., Collard, H. R., & Jones, M. G. (2017). Idiopathic pulmonary fibrosis. Lancet (London, England), 389(10082), 1941–1952. https://doi.org/10.1016/S0140-6736(17)30866-8
Thannickal, V. J., Toews, G. B., White, E. S., Lynch, J. P., 3rd, & Martinez, F. J. (2004). Mechanisms of pulmonary fibrosis. Annual review of medicine, 55, 395–417. https://doi.org/10.1146/annurev.med.55.091902.103810
Wallace, W., Fitch, P., Simpson, A. and Howie, S. (2006). Inflammation-associated remodelling and fibrosis in the lung - a process and an end point. International Journal of Experimental Pathology, 88(2), pp.103-110
Williamson, J. D., Sadofsky, L. R., & Hart, S. P. (2015). The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Experimental lung research, 41(2), 57–73. https://doi.org/10.3109/01902148.2014.979516
Zisman, D. A., Keane, M. P., Belperio, J. A., Strieter, R. M., & Lynch, J. P., 3rd (2005). Pulmonary fibrosis. Methods in molecular medicine, 117, 3–44. https://doi.org/10.1385/1-59259-940-0:003