MECHANISMS OF PULMONARY FIBROSIS

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from applicant's abstract and specific aims): Pulmonary fibrosis is a common end result of diverse forms of lung injury and interstitial lung diseases. Despite recent progress, the identity of cells responsible for elaboration of mediators driving the fibrosis process remains uncertain. The eosinophil has recently been identified as a major source for several key cytokines with fibrogenic activities, including monocyte chemotactic protein-1 (MCP-1) and transforming growth factor beta (TGF-b). It has also been identified as an important source of these and other cytokines in fibrotic lesions, while the importance of interleukin-5 (IL-5) in eosinophil recruitment have been demonstrated in allergic diseases. Human pulmonary fibrosis and fibrosis of the airway walls in asthma are associated with significant influx of eosinophils, and an increase in lung eosinophils indicates a worst prognosis and resistance to treatment in idiopathic pulmonary fibrosis. Despite this abundant suggestive evidence, direct demonstration of a role for eosinophils in pulmonary fibrosis is lacking. The central hypothesis of this project is that recruitment of eosinophils into the lung and their activation by IL-5 and other cytokines result in increased expression of fibrogenic cytokines such as TGF-b, which will in turn cause the recruitment, proliferation and activation of fibroblasts, which are ultimately responsible for the increased deposition of extracellular matrix in the fibrotic lung. To test this hypothesis, four specific aims are proposed: 1) measure lung eosinophil kinetics in a murine model of bleomycin-induced pulmonary fibrosis; 2) identify the chemotactic factors responsible for eosinophil recruitment and activation; 3) assess lung IL-5 expression, its regulation, and identify the cells responsible for IL-5 expression; 4) examine the role of IL-5 in pulmonary fibrosis by examining the effects of, a) neutralizing antibody to IL-5 and b) exogenous IL-5 administration.