34 Chapter 2 MMP28 MMP28 (epilysin), the newest member of the MMP family, has recently been identified as a possible biomarker for IPF [94]. Unlike other MMPs MMP28 is constitutively expressed in healthy tissue, including lung, leading to the suggestion that it has a role in maintenance of tissue homeostasis [104-106]. It is localized in bronchial and alveolar epithelial cells in IPF lung tissues [95] with the gene and protein levels being increased in IPF lung tissues, compared to other fibrotic lung diseases or normal controls, and the protein levels are increased in serum of IPF patients [66, 94, 95]. MMP28 is also expressed in macrophages and has been shown to reduce proinflammatory (M1) macrophage functions while promoting anti-inflammatory / profibrotic (M2) programming, thereby supporting development of lung fibrosis [107]. Interestingly, MMPs diffuse along ECM protein fibers, with different MMPs having affinity for different collagen fiber structures (for example MMP1, 8 or 13 unwind and cleave collagen fibers at specific internal sites within the fibers, whereas MMP2 and 9 will move along the fibers and digest predominantly at the termini) [108]. Through these patterns of behavior, the MMPs orchestrate a programmed functional outcome within a tissue environment. In a fibrotic environment, where the topography and arrangement of the ECM fibers is disrupted, the regulated function of the MMPs is predicted to be adversely affected. ECM FRAGMENTS IN LUNG FIBROSIS The resultant products from endogenous enzyme activity in the fibrotic lung environment, while often overlooked, are potentially key players in the disease process. These released fragments, called matricryptins or matrikines or ECM fragments (the term by which they will be referred to in this review), are bioactive and have been reported to regulate processes as diverse as cell signaling, gene expression, angiogenesis, adipogenesis, tumor growth and metastasis, wound healing and fibrosis. The ECM fragments can interact with growth factor receptors, toll-like receptors, integrins and other diverse cell surface receptors through which they actively induce cellular responses that often differ from events induced by their parent molecule. ECM fragments can also act as proteolytic enzymes or inhibitors of enzyme activity themselves or can be involved in the process of proenzyme activation. In all these functional capacities, ECM fragments may contribute to the disrupted ECM remodeling that is characteristic of the fibrotic lung, as summarized in Table 3.
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