TY - JOUR T1 - Role of integrin-mediated TGFβ activation in the pathogenesis of pulmonary fibrosis JF - Biochemical Society Transactions JO - Biochem Soc Trans SP - 849 LP - 854 DO - 10.1042/BST0370849 VL - 37 IS - 4 AU - Goodwin, Amanda AU - Jenkins, Gisli Y1 - 2009/08/01 UR - http://www.biochemsoctrans.org/content/37/4/849.abstract N2 - IPF (idiopathic pulmonary fibrosis) is a chronic progressive disease of unknown aetiology without effective treatment. IPF is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after epithelial injury, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial–mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine TGFβ (transforming growth factor β) plays a central role in this process. In normal lung, TGFβ is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major TGFβ-activation pathways involves integrins, and the role of the αvβ6 integrin has been particularly well described in the pathogenesis of IPF. Owing to the pleiotropic nature of TGFβ, strategies that inhibit activation of TGFβ in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated TGFβ activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with IPF.Abbreviations: COPD, chronic obstructive pulmonary disease; EMT, epithelial–mesenchymal transition; IPF, idiopathic pulmonary fibrosis; itgb6, β6 integrin subunit gene; LAP, latency-associated peptide; LPA, lysophosphatidic acid; LPAR2, LPA, receptor 2; LTBP, latent transforming growth factor-β-binding protein; MMP, matrix metalloproteinase; PAR-1, protease-activated receptor-1; TGFβ, transforming growth factor β ER -