Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal lung disease characterized by interstitial and alveolar accumulation of myofibroblasts, though little is known about the mechanism. Previous studies have shown that the survival factor, IGF-I, is expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that IGF-I protect myofibroblasts from apoptosis thereby leading to their accumulation in the lung. The goals of this proposal are: (i) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (ii) to investigate the mechanism of dyregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by two specific aims. Specific aim one will address the mechanisms through which IGF-I prevents apoptosis. The focus of these studies will include the mechanism of inactivation of the effector capsases (3, 6 and 7) and the potential role of anti-apoptotic proteins. In specific aim two, we will investigate the expression of antiapoptotic proteins in the lungs of patients with IPF/UIP. The findings from this work are expected to provide new insights into the mechanism of myofibroblast apoptosis and how this process is dysregulated in IPF/UIP.