Mechanisms of myofibroblast survival in fibrosis

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(Applicant's Abstract) Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal parenchymal lung disease characterized by interstitial and alveolar fibroproliferation and the appearance of myofibroblasts. Little is known about the mechanisms of myofibroblast accumulation in IPF/UIP or why they fail to be eliminated as occurs during normal wound repair. Previous studies from this and other laboratories have shown that survival factors, especially IGF-I, are abundantly expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that the presence of survival factors, including IGF-I, in the parenchyma and airspaces of patients with IPF/UIP protect myofibroblasts from apoptosis. Under these conditions, myofibroblasts are proposed to accumulate in numbers and can thus contribute to parenchymal fibrosis for extended periods of time. The major goals of this proposal are three-fold: (i) to investigate the conditions and mechanisms that mediate myofibroblast apoptosis under conditions of growth factor and stretch withdrawal; (ii) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (iii) to investigate the mechanism of dysregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by four specific aims. Specific aim one will address the role of growth factors, physical forces and IGF-I in myofibroblast differentiation, reversion to a fibroblast phenotype and apoptosis. These studies will form a basis for determining the mechanisms that promote myofibroblast apoptosis with a focus on the mechanisms of caspase activation (specific aim two). The objective of specific aim three is to uncover the mechanisms through which IGF-I prevents the initiation of the death program. 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. Lastly, in specific aim four, we propose to apply what has been learned from this studies conducted in this proposal to address the mechanisms that promote protection from apoptosis 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 becomes dysregulated in IPF/UIP.