37 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis ROLE OF ECM FRAGMENTS IN THE FIBROTIC PROCESS Active ECM fragments are generated throughout all phases of tissue repair and may contribute to the ongoing fibrotic process [117]. These fragments have roles in the regulation of the inflammatory responses (which have recently been reviewed in [111, 133], but will not be the subject of this review), angiogenic and fibrogenic responses. The altered ECM landscape in the fibrotic lung contains an increased proportion of many ECM molecules that yield active fragments that regulate angiogenesis (see Table 3). Given that angiogenesis generally precedes fibrosis in an area of tissue undergoing repair, these regulatory ECM fragments may impact the tissue repair as a result of the altered structure of the fibrotic ECM. In turn, the consequential sprouting of fresh vessels from pre-existing vasculature within the damaged tissues may also impact the dysregulated and aberrant ECM composition and the continuing production of active ECM fragments. Fibroblasts are recognized as the key active cell during the fibrogenic phase of the repair process. Aberrant fibroblast responses to the altered ECM environment that they encounter in the fibrotic lung may lead to overabundant ECM fragment production, which would further compound the matrix remodeling driving progressive fibrosis. The role of the ECM scaffold in IPF lung tissues has been elegantly illustrated [9, 24] as a driver of cellular responses; however, how this environment impacts the release of active ECM fragments has yet to be explored. Collagen type I The smallest identified ECM active fragment (PGP) comes predominantly from collagen type I but is also present in collagens type III and IV. The role of this fragment has been well characterized in inflammatory processes, as reviewed in [111], but less is known about its potential roles in regulating other processes in the angiogenic or fibrogenic responses. The collagen type I α1 fragment released following MMP 2 and 9 cleavage between amino acids 1158/1159 induces fibroblast migration and enhances deposition of a variety of ECM proteins, contributing to the fibrotic response [112]. Collagen type IV The six α chains that generate the heterotrimers of collagen type IV have all been characterized to release active ECM fragments, which are predominantly active in the regulation of neo-angiogenesis and -lymphangiogenesis. In addition to these functions these ECM active fragments also regulate the activity of mesenchymal 2
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