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Increased cellular proliferation and differentiation leads to Increased extracellular matrix deposition
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
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
Evidence Supporting this KER
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
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Blaauboer M et al. Extracellular matrix proteins: A positive feedback loop in lung fibrosis. Matrix Biology, 2014, 34, 170-178
- 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.
- 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).
- 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.
- 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
- Fang S et al. circHECTD1 promotes the silica-induced pulmonary endothelial-mesenchymal transition via HECTD1. Cell Death and disease, 2018, 9:396.
- 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)
- Hinz B. (2016a). Myofibroblasts. Experimental eye research, 142, 56–70. https://doi.org/10.1016/j.exer.2015.07.009
- Hinz B. (2016b). The role of myofibroblasts in wound healing. Current research in translational medicine, 64(4), 171–177. https://doi.org/10.1016/j.retram.2016.09.003
- 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.
- Hu, B., & Phan, S. H. (2013). Myofibroblasts. Current opinion in rheumatology, 25(1), 71–77. https://doi.org/10.1097/BOR.0b013e32835b1352
- Hu B et al. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am J Pathol, 2015, 185, 3066-3075
- Judge J et al. Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase. Am J Physiol Lung Cell Mol Physiol, 2015, 309, L879-L887
- Lai et al. Intranasal delivery of copper oxide nanoparticles induces pulmonary toxicity and fibrosis in C57BL/6 mice. Scientific Reports, 2018, 8:4499
- 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
- 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.
- 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.)
- 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
- Ueha, S., Shand, F. H., & Matsushima, K. (2012). Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Frontiers in immunology, 3, 71. https://doi.org/10.3389/fimmu.2012.00071
- 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
- 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