31 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis Table 2: Different types of MMPs, their origins, involvement in lung fibrosis and possible mechanisms of action. Substrates for cleavage sourced primarily from [62]. (continued) MMP Source in vivo Localization in lung tissue Profile in lung fibrosis Substrates for Cleavage Possible mechanism of action References MMP10 Stromelysin 2 Bronchial and AECs and alveolar macrophages AECs, macrophages, and peripheral bronchiolar epithelial cells ↑ in serum and BAL from IPF ↑ protein in lung tissue from IPF ECM substrates Aggrecan; Fn; Ln; collagen types III, IV and V; link protein, gelatin, Non-ECM substrates lamin, casein, Pro-1, 8, 10 Possible role in regulation of macrophage migration and polarization driving fibrotic response [58, 86-88] MMP12 Macrophage elastase macrophages, and lung stromal cells Not available ↑ in plasma and BAL from IPF ↑ fragment from collagen type IV released after MMP12 degradation in IPF ECM substrates Elastin; aggrecan; Fn; collagen type IV; osteonectin; Ln; nidogen Non-ECM substrates Plasminogen; apolipoprotein(a) Postulated disrupted integrity of sub-epithelial/ endothelial basement membrane resulting in infiltration of factors and interstitial cells to the alveolar space promoting fibro-proliferative response [67, 89, 90] MMP13 Collagenase 3 Bronchial and AECs, alveolar macrophages and fibroblasts Bronchial and AECs and alveolar macrophages ↑ in plasma from IPF ↑ protein in lung homogenates from IPF ECM substrates Collagen types I, II, III, IV, IX, X and XIV; aggrecan; Fn; tenascin; osteonectin; Ln; Perlecan Non-ECM substrates CTGF; ProTGF-β; MCP-3; α1antichymotrypsin Not known as yet [67, 91] MMP14 MT1-MMP AECs, alveolar macrophages and endothelial cells. AECs and alveolar macrophages ↑ gene and protein in lung tissue from IPF ECM substrates Collagen types I, II and III; gelatins; aggrecan; Fn; Ln; fibrin; Ln-5 Non-ECM substrates ProMMP-2; proMMP-13; CD44; MCP-3; tissue, transglutaminase Facilitates fibroblast migration through disruption of ECM barriers [69, 70, 92] 2
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