39 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis Fibronectin Fibronectin is recognized to have central roles in regulating fibroblast migration when incorporated in the ECM, while the released active fragments of fibronectin also regulate fibroblast functions, including their phenotype differentiation [117]. These fragments also regulate endothelial cell responses, particularly during wound healing and possibly fibrosis. Anastellin, a peptide derived from the first type III module in fibronectin, helps orchestrate fibronectin fibriilogenesis and is anti-angiogenic but promotes fibroblast survival [142]. Fibulin-1 Fibulin-1 usually acts as a bridging molecule in the ECM facilitating the assembly of the larger structural proteins to which it binds, including collagen type I, elastin and fibronectin. In vitro studies have identified a peptide from fibulin-1 that activates lung-derived fibroblasts, inducing attachment, enhanced viability, proliferation and mitochondrial activity [131]. Fibulin-1 levels are increased in serum and lung tissues of IPF patients, with high levels being related to disease progression [47]. Mice that lack the fibulin-1C isoform are protected from the development of pulmonary fibrosis, through regulation of TGF-β activation via interactions with latent TGF-β binding protein [46, 132], but the levels of circulating fragments from fibulin-1 have not been measured in these animals. Perlecan When incorporated in the basement membrane, perlecan is recognized to have a proangiogenic function. However, when the active fragment, endorepellin, is released from its parent molecule, it has the opposite effect. Through binding to integrin α2β1 on endothelial cells, endorepellin mediates interruption of cell migration, via disruption of cytoskeletal arrangement and focal adhesions [143]. Endorepellin cooperates with endostatin, a polypeptide derived from the carboxy-terminus of collagen type XVIII, to enhance the effectiveness of each ECM fragment [130]. It also interacts with fibroblasts, protecting them from apoptosis, hence possibly mediating a role in fibrosis through this promotion of fibroblast survival [129]. ECM fragments as (bio)markers of an active fibrotic process In addition to being active contributors to the pathological processes occurring during lung fibrosis, ECM fragments can also serve as sentinel indicators of these processes. During the cleavage processes that result in the release of ECM fragments from the deposited ECM in lung tissues, or indeed during the processes that enable the ECM fibers to be incorporated into the ECM bed, neo-epitopes are exposed on these fragments. Monitoring of the exposure of these neo-epitopes, or the levels of 2
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