28 Chapter 2 In fibrotic lung disease, an easy assumption would be that there would be reduced levels of matrix degradative enzymes, in particular MMPs, as this is where the greatest amount of research has focused, as an explanation as to why there is increased ECM deposition. However, multiple studies report increased levels of several MMPs associated with fibrotic lung disease, reviewed in [53, 57, 58]. While this appears paradoxical, it is important to realize that in addition to degrading ECM proteins, the range of substrates MMPs can process and activate includes cell receptors, chemokines and growth factors [59]. Through the generation of chemotactic gradients or activation of specific proinflammatory or profibrotic factors, in cooperation with disruption of basement membranes and other physical barriers within the tissue, MMPs can influence the influx of inflammatory cells into the site of tissue injury, which in turn then contribute to the development / perpetuation of fibrosis [60, 61]. A number of MMPs have been specifically linked to fibrosis in the lungs, summarized in Table 2. A selection of MMPs associated with fibrotic lung disease, particularly IPF, are highlighted herein. MMP1 MMP1, considered a “classic” collagenase, cleaves interstitial collagens including collagen type I and III. MMP1 protein levels are increased in bronchial alveolar lavage and gene and protein expression levels are increased lung tissue from IPF, compared to non-fibrotic, patients [63, 69, 79, 96]. A single nucleotide polymorphism, within the AP-1 binding domain of the MMP1 promoter (which increases transcription of MMP1) is observed more frequently in patients with IPF who smoke, than those who do not [97]. In a murine system, MMP1 enhanced cellular migration, increased wound closure rate, and protected cells from apoptosis. Increased MMP1 in alveolar epithelial cells repressed mitochondrial respiration, reduced the production of reactive oxygen species (both total and mitochondrial) and also, under normoxic conditions, increased expression of hypoxia-inducible factor-1α (HIF-1α) [98]. The fact that MMP1 was upregulated via increased HIF-1α induction under hypoxic conditions in the alveolar epithelial cells suggests a role for MMP1 in bidirectional cross talk regulating alveolar epithelial cell functions in fibrosis. Intriguingly, MMP1 has recently been reported to be part of a set of signature genes illustrating the link between IPF and lung cancer. MMP1 was suggested to be a promising candidate gene driving significant expression changes through the transition from healthy tissue to IPF and non-small cell carcinoma [99]. MMP1 is primarily located in reactive bronchial epithelial cells, hyperplastic type 2 pneumocytes in honeycomb cysts and in alveolar macrophages, with little to no expression being observed in interstitial mesenchymal cells, suggesting that the localization of the increased MMP1 in fibrotic lung tissue does not facilitate the degradation of the fibrotic deposits [69].
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