mechanisms of this disease will translate into more effective treatments. Mounting evidence implicates repetitiveimicroinjurystorthealveolarepithelium followed by aberrant wound repair as the predominant mechanism of disease pathogenesis; Defects (both genetic and acquired) in type II alveolar epithelial cells increase the susceptibility of these cells to injury and apoptosis and also interfere:withtheir-regenerativercapacity, For example, genetic mutations in type I alveolar epithelial cell-specific proteins, including surfactant proteins A and C, have been identified in individuals with familial pulmonary fibrosis. These mutations result in protein defects that induce cell stress and promote cell death Furthermore, mutations in telomere maintenance genes (including TERT and TERC) result in telomere shortening and impair the regenerative capacity of the type II alveolar epithelium. In addition to these genetic studies, histopathologic and biomarker studies of IPF patients consistently identify abnormalitiesimthe alveolar epithelium, including denudation and/or hyperplasia of cells in areas of active fibrosis and elevated systemic levels of surfactant proteins. Finally, animal studies confirm that a targeted injury to the type II alveolar epithelial cell is sufficient to cause fibrosis. It is currently unknown what environmental challenges are responsible for the repetitivemicroinjury:torthersusceptibletypeil alyeolarepithelialycell\(hencestheridiopathicwdesignation); It is likely that multiple different insults contribute. For example, both animal models and human studies implicate chronic berpeswirus infection as an important etiologic factor in a subset of patients. Furthermore, acute viral infections likely contribute to acute exacerbations of the disease. Following epithelial injury, fibroblasts accumulate in the lung interstitium and typically differentiate into myofibroblasts. Myofibroblasts are highly contractile and contribute to tissue destruction. They are also responsible for the synthesis and deposition of extracellular matrix proteins such as fibronectin and collagen. In normal wound healing, fibroblasts undergo apoptosis following the successful restoration of an intact epithelium. Imicontrasty(myo)fibroblastsjin"lPPrare resistant to apoptotic stimuli, favoring their persistence and ultimately contributing/to:the:progressive mature oftherdisease. How epithelial injury initiates (myo)fibroblast activation is an area of ongoing study. However, current evidence suggests that the damaged type II alveolar epithelial cells secrete profibrogenic mediators, including transforming growth factor-B (TGE-B). connective tissue growth factor, and platelet-derived growth factor. Disruptiomof , activation of the clotting cascade, and generation of thrombin, which can activate fibroblasts through cleavage of protease-activated receptors. In turn, the fibrogenic mediators, in conjunction with the development of a stiff, cross-linked, collagen-