A growing body of evidence indicates that elcosanoid metabolites of arachidonic acid modulate the inflammatory, immune, and mesenchymal components contributing to pulmonary fibrosis. However, leukotrienes (LTs) promote all of these processes while prostaglandin E-, (PGE2) generally suppresses them. Of note, our laboratory has identified two separate abnormalities in eicosanoid synthesis in the lungs of patients with the fibrotic disease, idiopathic pulmonary fibrosis: namely, overproduction of LTs and underproduction of PGE2- Moreover, additional recent studies indicate that a similar eicosanoid imbalance characterizes animal models of pulmonary fibrosis, and that modulation of this imbalance by genetic or pharmacologic means attenuates fibrogenesis. The hypothesis of this proposal is that this pro-fibrotic imbalance of eicosanoid generation is centrally important in the pathogenesis and prognosis of pulmonary fibrosis. Furthermore, we hypothesize that this eicosanoid imbalance is exacerbated by treatment with corticosteroids, contributing to the disappointing clinical response of fibrotic lung diseases to these agents.
The aims of the current proposal are to extend our understanding of the cellular and enzymatic mechanisms underlying this imbalance, its amenability to pharmacologic and/or genetic modulation, and the cytokines and (growth factors regulated by eicosanoids which influence the evolution of fibrotic lung disease. This will be accomplished by studying lung tissue and cells (macrophages and fibroblasts) from mice with bleomycin induced pulmonary fibrosis and from patients with pulmonary fibrosis. In the clinical studies proposed, eicosanoid abnormalities will be correlated with clinical severity, histologic classification, and course of disease. In addition, we will determine the effects of three treatment regimens for pulmonary fibrosis (prednisone, azathioprine plus prednisone, or the LT synthesis inhibitor zileuton) on eicosanoid synthesis, pathobiological mechanisms, and clinical outcomes. The proposed studies will critically evaluate a new pathophysiologic paradigm with important implications for therapy of this devastating group of fibrotic lung diseases.
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