The pathogenesis of the inflammation and fibrosis that develop in idiopathic pulmonary fibrosis remains to be fully delineated, and effective treatments for this progressive disease are needed. The planned studies are based on a series of findings indicating that eosinophils are important, previously unrecognized, cellular participants in the pathogenesis of pulmonary fibrosis. With sensitive staining techniques, eosinophils are demonstrable in appreciable numbers in the pulmonary interstitium in both human idiopathic pulmonary fibrosis and in murine models of pulmonary inflammation and fibrosis. Eosinophils, which have role normal wound healing responses, are sources of several fibrogenic cytokines. Analyses of human samples demonstrate eosinophils to account for almost 90% of cells expressing mRNA transcripts for cytokine transforming growth factor-beta1. The planned studies will utilize both human and murine tissues and cells to evaluate the roles of eosinophils in the development of pulmonary fibrosis. Studies with human tissues and cells will evaluate the prevalence of eosinophils in tissues obtained by open lung biopsy with biopsied human lung tissues will evaluate the contributions of eosinophils and other cells as source pro-inflammatory and fibrotic cytokines. The capacity of eosinophils to elaborate various fibrotic cytokines and the mechanisms regulating that elaboration will be studied with isolated human eosinophils. Studies utilize the murine model of bleomycin-induced pulmonary inflammation and fibrosis to evaluate the roles of eosinophils as sources of fibrotic cytokines in the temporal evolution of pulmonary injury and to investigate potential interventions to interrupt the recruitment and activation of eosinophils and other leukocytes pulmonary lesions. These investigations of human and experimental pulmonary fibrosis will aim to define the roles of eosinophils in the progression of the inflammatory and fibrotic responses in pulmonary fibrotic diseases. Understanding these roles and investigating modalities that may modulate the functioning eosinophils will be pursued in the broader context of delineating the evolution of the progressive inflammatory process that leads to pulmonary fibrosis. From these studies, new understanding of pathogenesis of pulmonary fibrotic diseases will be obtained and potential new therapeutic approaches of pulmonary fibrosis will be evaluated.
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