38 Chapter 2 cells. While most of the information about these functions have been elucidated in the cancer field, emerging evidence points to key roles for these fragments in pulmonary diseases. Arresten (α1 non-collagenous region 1 (NC1)) binds to integrin α1β1 to inhibit angiogenesis through impacting endothelial cell migration, proliferation and the ability to form tubes. These actions occur in part by blocking its parent molecule binding to the same integrin. [134]. Arresten may also interact with heparan sulfate proteoglycans to further enhance its effects. Arresten is increased in lung tissue of patients with usual interstitial pneumonia (UIP) [118]. Canstatin (α2 NC1) binds to integrins αvβ1, αvβ3 and αvβ5 on endothelial cells to inhibit tumor associated angiogenesis through disrupting cell-matrix interactions. Some studies suggest that interactions with αvβ3 and αvβ5 induces apoptosis, while inhibiting migration and proliferation in the endothelial cells [135]. Canstatin is also increased in lung tissue of patients with usual interstitial pneumonia (UIP) [118]. Tumstatin (α3 NC1) binds to the CD47/αvβ3 integrin complex to inhibit proliferation of melanoma and epithelial cells. It inhibits neo-angiogenesis but also has antitumorigenic activities that are associated with distinct regions within this active ECM fragment [136]. Tumstatin binds to airway smooth muscle cells to influence the ECM they deposit, which in turns impacts the migration of endothelial or inflammatory cells within this matrix environment [137, 138]. The levels of tumstatin are reduced in airway tissues from individuals with asthma and lymphangioleiomyomatosis [114, 139], and recently were reported to undetectable in lung tissues from patients with UIP [118]. Similarly, tetrastatin (α4 NC1) and hexastatin (α6 NC1) also bind to integrins (αvβ3 and αvβ1, αvβ3 and αvβ5 respectively). While the direct integrin that lamstatin/ pentatstatin (α5 NC1) interacts with has not been reported, it is reasonable to assume this active ECM fragment will also interact in a similar manner to its family members. Similar to tumstatin, lamstatin/pentastatin has been reported to be absent in lung tissues from patients with lymphangioleiomyomatosis and UIP [118, 139]. Arresten, canstatin and tumstatin all interact directly with fibroblasts to exert organspecific effects on migration and proliferation [140], with induction of migration being noted in cardiac fibroblasts but inhibition in lung fibroblasts [118, 141]. In the lung fibroblasts, TGF-β induced conversion of fibroblasts to myofibroblasts was linked with canstatin release.
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