33 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis MMP3 MMP3, also known as stromelysin-1, can degrade a variety of ECM proteins including collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, elastin, and laminin. MMP3 levels are increased in IPF patients with progressive disease who died within three years of follow-up, compared to those who survived [72]. Both MMP3 gene and protein expression are increased in IPF patients’ lung tissue and serum compared to controls [73, 74]. MMP3 is predominantly expressed in regions of bronchiolization close to aberrant ECM deposits within the IPF lung tissue, with some evidence of weaker expression in lymphoid aggregates [74]. MMP3 is important for regulating the activation of the profibrotic growth factor TGF-β through facilitating the release of TGF-β homodimer from the latency associated peptide and latent TGF-β binding protein 1 [75]. Also of importance for the development of fibrosis in the lungs, MMP3 can induce gene and protein expression of connective tissue growth factor (CTGF/ CCN2), independent of its proteolytic activity [76, 77]. MMP7 Increased levels of MMP7, referred to as matrilysin, have been recognized as a biomarker for IPF [100, 101]. Increases in serum and plasma protein levels and in lung tissue gene and protein expression are well documented in IPF patients compared to healthy controls or other forms of fibrotic lung disease [63, 65, 67, 78, 79]. Two MMP7 promoter polymorphisms (rs11568818 and rs11568819), which result in higher levels of MMP7 in plasma, have been associated with IPF [102]. MMP7 is synthesized and released from lung bronchial epithelial cells and aberrantly activated alveolar epithelial cells, mononuclear phagocytes and circulating fibrocytes [65, 68]. It has proteolytic activity against a wide range of ECM proteins including collagen type IV, laminin, elastin and fibronectin. In addition, it cleaves gelatin, osteopontin (a multifunctional cytokine which controls cell adhesion and migration), transmembrane tumor necrosis factor α (pro-TNF-α), β4 integrin, E-cadherin, syndecan, FAS ligand (FasL), plasminogen and insulin-like growth factor binding protein-3 (IGFBP-3), among others [57, 103]. MMP7 colocalizes with osteopontin in alveolar epithelial cells in IPF tissues and has an important role in regulating neutrophil transepithelial influx via the shedding of syndecan-I-CXCL1 complexes, thereby facilitating epithelial cell damage which then promotes fibrosis [80, 81]. The cleavage of FasL from the IPF fibroblast surface (releasing sFasL into the circulatory system), and thus protecting the fibroblast from undergoing apoptosis induced by T cells, has also recently been suggested as a mechanism by which MMP7 contributes to the development of fibrosis [82]. 2
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