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Relationship: 1707


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 cellular proliferation and differentiation leads to Increased extracellular matrix deposition

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

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

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

When activated, fibroblasts migrate to the site of tissue injury and build a provisional ECM, which is then used as a scaffold for tissue regeneration. Activated fibroblasts in turn produce IL-13, IL-6, IL-1β and TGFβ, propagating the response. In the second phase, which is the proliferative phase, angiogenesis is stimulated to provide vascular perfusion to the wound. During this phase more fibroblasts are proliferated and they acquire a-smooth muscle actin expression and become myofibroblasts. Thus, myofibroblasts exhibit features of both fibroblasts and smooth muscle cells. The myofibroblasts synthesise and deposit ECM components that eventually replace the provisional ECM. Because of their contractile properties, they play a major role in contraction and closure of the wound tissue (Darby et al., 2014). Apart from secreting ECM components, myofibroblasts also secrete proteolytic enzymes such as metalloproteinases and their inhibitors tissue inhibitor of metalloproteinases, which play a role in the final phase of the wound healing which is scar formation phase or tissue remodelling.

During this final phase, new synthesis of ECM is suppressed to allow remodelling. The wound is resolved with the secretion of procollagen type 1 and elastin, and infiltrated cells including inflammatory cells, fibroblasts and myofibroblasts are efficiently removed by cellular apoptosis. However, in the presence of continuous stimulus resulting in excessive tissue damage, uncontrolled healing process is initiated involving exaggerated expression of pro-fibrotic cytokines and growth factors such as TGFβ, excessive proliferation of fibroblasts and myofibroblasts, increased synthesis and deposition of ECM components, inhibition of reepithelialisation, all of which lead to replacement of the normal architecture of the alveoli and fibrosis (Ueha et al., 2012; Wallace et al., 2006).

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 of this KER is high. There is an accepted mechanistic relationship between activated myofibroblasts, and the capacity to secrete collagen (Hinz, 2016a; Hinz, 2016b; Hu & Phan, 2013).

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

Several studies have shown that inhibition of TGF-β involved in fibroblast activation and collagen deposition results in attenuated fibrotic response in lungs; however, results are inconsistent. More studies are required to support the quantitative KER.

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
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


List of the literature that was cited for this KER description. More help
  1. Blaauboer M et al. Extracellular matrix proteins: A positive feedback loop in lung fibrosis. Matrix Biology, 2014, 34, 170-178
  2. Bonniaud, P., Kolb, M., Galt, T., Robertson, J., Robbins, C., Stampfli, M., Lavery, C., Margetts, P., Roberts, A. and Gauldie, J. (2004).Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis. The Journal of Immunology,173(3), pp.2099-2108.
  3. Cao, H., Wang, C., Chen, X., Hou, J., Xiang, Z., Shen, Y. and Han, X. (2018). Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis. Scientific Reports, 8(1).
  4. Chen, Y., Zhang, X., Bai, J., Gai, L., Ye, X., Zhang, L., Xu, Q., Zhang, Y., Xu, L., Li, H. and Ding, X. (2013). Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial–mesenchymal transition and fibroblast activation. Cell Death & Disease, 4(6), pp.e665-e665.
  5. Dong J et al. TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation. Nanotoxicology, 2017, 11(1), 41-51
  6. Fang S et al. circHECTD1 promotes the silica-induced pulmonary endothelial-mesenchymal transition via HECTD1. Cell Death and disease, 2018, 9:396.
  7. Guan, R., Wang, X., Zhao, X., Song, N., Zhu, J., Wang, J., Wang, J., Xia, C., Chen, Y., Zhu, D. and Shen, L. (2016). Emodin ameliorates bleomycin-induced pulmonary fibrosis in rats by suppressing epithelial-mesenchymal transition and fibroblast activation. Scientific Reports, 6(1)
  8. Hinz B. (2016a). Myofibroblasts. Experimental eye research, 142, 56–70.
  9. Hinz B. (2016b). The role of myofibroblasts in wound healing. Current research in translational medicine, 64(4), 171–177.
  10. Hoyt, D. G., & Lazo, J. S. (1988). Alterations in pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor-beta precede bleomycin-induced pulmonary fibrosis in mice. The Journal of pharmacology and experimental therapeutics, 246(2), 765–771.
  11. Hu, B., & Phan, S. H. (2013). Myofibroblasts. Current opinion in rheumatology, 25(1), 71–77.
  12. Hu B et al. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am J Pathol, 2015, 185, 3066-3075
  13. Judge J et al. Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase. Am J Physiol Lung Cell Mol Physiol, 2015, 309, L879-L887
  14. Lai et al. Intranasal delivery of copper oxide nanoparticles induces pulmonary toxicity and fibrosis in C57BL/6 mice. Scientific Reports, 2018, 8:4499
  15. Li, M., Krishnaveni, M., Li, C., Zhou, B., Xing, Y., Banfalvi, A., Li, A., Lombardi, V., Akbari, O., Borok, Z. and Minoo, P. (2011). Epitheliumspecific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. Journal of Clinical Investigation, 121(1), pp.277-287
  16. Li et al. Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin. Am J. Physiol Lung Cell Mol Physiol, 2017, 313: L80-L91.
  17. Ma J et al. Role of epithelial-mesenchymal transition (EMT) and fibroblast function in cerium oxide nanoparticles-induced lung fibrosis. Toxicol Appl Pharmacol, 2017, 323: 16-25.)
  18. Osterholzer J et al.Implicating exudate macrophages and Ly-6Chigh monocytesin CCR2 Dependent lung fibrosis following gene-targeted alveolar injury. J Immunol, 2013, 190, 7, 3447-3457
  19. Ueha, S., Shand, F. H., & Matsushima, K. (2012). Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Frontiers in immunology, 3, 71.
  20. 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
  21. Yi, E., Bedoya, A., Lee, H., Chin, E., Saunders, W., Kim, S., Danielpour, D., Remick, D., Yin, S. and Ulich, T. (1996). Radiation-induced lung injury in vivo: Expression of transforming growth factor?Beta precedes fibrosis. Inflammation, 20(4), pp.339-352