30 Chapter 2 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 MMP7 Matrilysin Bronchial epithelial cells, aberrantly activated AECs, mononuclear phagocytes and fibrocytes Aberrant activated AECs and in bronchiolar epithelial cells ↑ in plasma and serum from IPF ↑ gene and protein in IPF lung tissue ECM substrates Aggrecan; gelatins; Fn; Ln; elastin; entactin; collagen type IV; tenascin; decorin; link protein, Non-ECM substrates osteopontin, β4 integrin, E-cadherin, syndecan, FasL, plasminogen, Proα-defensin; proTNFα; CTGF; HB-EGF; RANKL; IGFBP-3; plasminogen Regulating neutrophil transepithelial influx, via the shedding of syndecani-CXCL1 complexes, Protecting the fibroblast from undergoing apoptosis vis removal of FasL from their surfaces [63, 65-68, 72, 78-82] MMP8 Collagenase 2 Bronchial epithelial cells, neutrophils, macrophages Bronchial epithelial cells in regions of moderately severe and severe fibrosis, macrophages Type II AECs are positive for MMP-8 in control lung tissue but there is minimal or no staining in these cells in regions of moderately severe and severe fibrosis in IPF lungs ↑ in plasma and BAL from IPF ↑ gene and protein in lung homogenates and tissue from IPF ECM substrates Collagen types I, II and III; gelatins; aggrecan; link protein Non-ECM substrates α1-PI Promotes fibrocyte migration [58, 66-68, 72, 83, 84] MMP9 Gelatinase B AECs, neutrophils, macrophages, fibrocytes and fibroblasts in fibroblastic foci Metaplastic AECs, alveolar and interstitial macrophages and fibroblasts in fibrotic foci ↑ in plasma from IPF ↑ gene and protein in lung tissue from IPF ECM substrates Gelatins; collagen types III, IV and V; aggrecan; elastin; entactin; link protein, vitronectin; N-telopeptide of collagen type I Non-ECM substrates ProTGF-β; IL-2 receptor α; Kit-L; IGFBP-3; proIL-1β; ICAM-1; α1-PI; galectin-3; plasminogen Fibroblasts in healthy lung tissue express Thy-1 (a glycophosphatidylinositollinked glycoprotein) which suppresses MMP9 expression. IPF fibroblasts lack Thy-1 leading to expression of MMP9, which correlates with regions of active fibrogenesis, suggesting a role for MMP9 in induction of fibrosis. Activation of TGF-β1 in the extracellular space [67-69, 72, 79, 85]
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