27 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis It is not unlikely that the ECM in fibrotic lung disease would have enhanced storage capacity for bioactive factors as a result of the increased amount of the abovementioned ECM proteins, among others, and the activation and release of these factors from the ECM would be boosted by the biomechanical changes in the tissues in lung fibrosis. Further investigations regarding the ECM-stored bioactive factors are necessary for improving our understanding of the contribution of the repository function of the ECM to the progression of lung fibrosis. Collective impact of the altered ECM scaffold in fibrotic lung disease All in all, the altered ECM in fibrosis generates diverse influences which impact cellular phenotypes; as summarized in Table 1. While the biochemical changes in the fibrotic microenvironment have been demonstrated with proteomics analyses via mass spectrometry [6], the accompanying biomechanical changes, such as increase in stiffness or loss of viscoelastic relaxation [10], require further investigation. While these changes could be simply the result of the altered biochemical composition, there are other emerging contributing factors such as collagen crosslinking that require further clarification. With the new developments in the field of biomaterials, advanced in vitro culture systems will be generated to mimic the specific biomechanical properties of the fibrotic microenvironment. Such systems will further improve our understanding of how the biomechanical properties of the ECM, either individually or collectively, contribute to the perpetuation of fibrotic disease in the lung. Eventually, such knowledge should illuminate how such properties could be targeted via therapeutic intervention for treatment of lung fibrosis. BEYOND THE ECM SCAFFOLD The role of ECM degrading enzymes and their regulators The ECM is a dynamic microenvironment that is constantly being remodeled as elements are degraded and newly deposited during normal tissue maintenance and particularly under conditions of disease pathogenesis. While all cell types synthesize, secrete and orchestrate deposition of ECM (including epithelial cells, mesenchymal cells, endothelial cells and immune cells), the fibroblasts are recognized as the major ECM producing cell type in fibrotic tissues. Leukocytes and macrophages, but also mesenchymal and epithelial cells produce enzymes that regulate the degradation of the ECM. The most well recognized group are the matrix metalloproteinases (MMPS), but also serine or cysteine proteases have a role in maintaining a healthy homeostasis within the ECM [52, 53]. Activity of the enzymes that degrade the ECM is tightly balanced by endogenous inhibitors (tissue inhibitors of MMPs (TIMPs)), serpins or cystatins [54-56]. 2
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