Mechanisms of myofibroblast death in pulmonary fibrosis

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DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF/UIP) is a fibrosing interstitial lung disease characterized by the accumulation and persistence of myofibroblasts in the lung parenchyma. Fifty percent of patients with biopsy proven IPF/UIP die within three years of diagnosis. There is no known effective therapy. While much has been learned about the origin of myofibroblasts in pulmonary fibrosis, little is known about the mechanism(s) that promote their persistence. We hypothesize that myofibroblasts persist in IPF/UIP, in part, by a failure to eliminate these cells by apoptosis. Preliminary studies show that pulmonary fibroblasts and myofibroblasts are basally resistant to apoptosis and that this resistance is overcome by exposure to the pro-inflammatory cytokines, TNF-( and IFN-(. Understanding the molecular basis of the basal resistance to apoptosis and its reversal is expected to provide new insights into how myofibroblast apoptosis may be therapeutically-manipulated in IPF/UIP. We hypothesize that the induction of pulmonary myofibroblast apoptosis involves two steps: 1) TNF-( and IFN-(-initiated sensitization and 2) Fas-ligation. In Specific Aim 1, we will test the hypothesis that the resistance of myofibroblasts to Fas-induced apoptosis is mediated by FAP-1, an inhibitory protein that basally interacts with Fas to prevent ligand-initiated recruitment of the adapter protein, FADD. In Specific Aim 2, we will address the mechanism by which sensitization by TNF-( and IFN-( overcomes the basal resistance of fibroblasts and myofibroblasts to apoptosis. The goal of Specific Aim 3 is to address the role of TNF-( and IFN-( in myofibroblast apoptosis in vivo and in the resolution of developing and previously established pulmonary fibrosis. Collectively, these studies are expected to provide novel insights into the relationship between pulmonary inflammation and fibrosis and how these events may be manipulated to slow or reverse the relentless progression of this usually fatal disorder.