29 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]. MMP Source in vivo Localization in lung tissue Profile in lung fibrosis Substrates for Cleavage Possible mechanism of action References MMP1 Collagenase 1 Bronchial and AECs Macrophages Reactive bronchial epithelial cells, hyperplastic type 2 pneumocytes in honeycomb cysts and in alveolar macrophages ↑ in plasma, serum & BAL from IPF, ↑ gene and protein in IPF lung tissue ECM substrates: Collagen types I, II, III, VII and X; gelatins; aggrecan; link protein; entactin; tenascin; perlecan Non-ECM substrates α2-M; α1-PI; α1antichymotrypsin; IGFBP-2, 3, 5; proIL-1β; CTGF Regulates AEC migration, wound closure and resistance to apoptosis. Possible bidirectional cross talk (via HIF1α) regulating AEC functions in fibrosis [63-67] MMP2 Gelatinase A Bronchial and AECs, Fibroblasts and fibrocytes Subepithelial myofibroblasts foci, close to basement membrane disruption. In ECM surrounding fibroblast foci. AECs and basal bronchiolar epithelial cells ↑ in plasma and BAL from IPF ↑ protein in IPF lung tissue ECM substrates Gelatins; collagen types IV, V, VII, X and XI; Ln; Fn; elastin; aggrecan; link protein Non-ECM substrates ProTGF-β; FGF receptor I; MCP-3; IGFBP-5; proIL-1β; galectin-3; plasminogen 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 [67-71] MMP3 Stromelysin 1 Bronchial and AECs, Alveolar Macrophages, and fibroblasts Regions of bronchiolization close to aberrant ECM deposits Weaker expression in lymphoid aggregates ↑ in plasma and BAL from IPF ↑ gene and protein in IPF lung tissue ECM substrates Aggrecan; decorin; gelatins; Fn; Ln; collagen types III, IV, IX and X; tenascin; link protein; perlecan Non-ECM substrates lamin, casein, IGFBP-3; proIL-1β; HB-EGF; CTGF; E-cadherin; α1antichymotrypsin; α1-PI; α2-M; plasminogen; uPA; proMMP-1, 7, 8, 9, 13 Regulating activation of TGF-β through release from latency associated peptide and latent TGF-β binding protein 1 Induction of CTGF [67, 72-77] 2
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