The role TNF-alpha and Macrophages in the Resolution of 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. While much has been learned about the origin of myofibroblasts in pulmonary fibrosis, little is known about the mechanism(s) that promote their persistence. Recent studies in human IPF/UIP patients and in animal models of this disease have suggested that: (i) fibrosis can progress in the absence of a robust inflammatory response, and (ii) fibrosis and sub-pleural honeycombing are worsened in the absence of the pro-inflammatory cytokine, TNF-a. These findings raise two fundamental questions: 1) Can alterations in pulmonary TNF-a expression be exploited to resolve pulmonary fibrosis? 2) Are macrophages, a key cell type implicated in TNF-a production in the lung, involved in the resolution of fibrosis via the production of TNF-a? The overall goal of this F32 application is to investigate these questions. It is hypothesized that (i) myofibroblast apoptosis requires a conditional sequence of signals initiated by macrophage-derived TNF-a, and (ii) restoration of TNF-a production during fibrosis will resolve the fibrotic response. The central hypotheses will be addressed by two specific aims. The goal of aim one is to investigate the potential role of macrophages in the endogenous production of TNF-a during the resolution of pulmonary fibrosis. The goal of aim one is to investigate the role of TNF-a in promoting the resolution of pulmonary fibrosis. Relevance to Public Health Fifty percent of patients with biopsy proven IPF/UIP die within three years of diagnosis and there is no known effective therapy. The proposed studies are expected to provide novel insights into the relationship between lung inflammation and fibrosis and how these events may be manipulated to slow or reverse the relentless progression of this usually fatal disorder.