Mechanisms of Pulmonary Fibrosis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Pulmonary fibrosis is a common end result of diverse forms'of lung injury and interstitial lung diseases. A complex interplay between certain lung cells is known to be important in the fibrotic process, although the exact identity of the cells and their precise in vivo roles have not been unequivocally determined. The eosinophil is found in many fibrotic conditions and lesions, and is known to express several key cytokines with fibrogenic activities, including monocyte chemotactic protein-1 (MCP-1), transforming growth factors a (TGFa) and (}(TGFp). It thus represents a potentially important source of such cytokines in these fibrotic lesions, thus identifying a potential role for eosinophils in fibrogenesis. Tissue recruitment of eosinophils is found to be dependent on interleukin-5 (IL-5) and several CC type chemokines, especially eotaxin. 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 suggestive evidence, the role of eosinophils in pulmonary fibrosis requires further elucidation. The central hypothesis of this proposal is that recruitment of eosinophils into the lung and their activation by certain chemokines/cytokines result in increased expression of fibrogenic cytokines such as TGFP, which will in turn cause the recruitment, proliferation and activation of fibroblasts with differentiation to myofibroblasts. These latter cells are ultimately responsible for the increased deposition of extracellular matrix in the fibrotic lung. To test this hypothesis, four specific aims are proposed: 1) characterize the elaboration of eotaxin and related CC chemokines in a rodent model of bleomycin-induced pulmonary fibrosis and identify the cells responsible for elaboration of injury-induced chemokines, and examination of associated regulatory mechanisms;2) determine the role of these chemokines in pulmonary fibrosis and eosinophil recruitment, activation and apoptosis, using neutralizingantibodies (to chemokines and cognate receptors) and transgenic knockout mice;3) analyze the regulatory role of eosinophils on fibroblast activation and myofibroblast differentiation in vitro, and identify the mediators involved, and 4) examine the ability of exogenous eotaxin and/or IL-5 treatment (as well as by IL-5 transgenic over-expression), and transferred eosinophils from fibrotic lungs, to exacerbate pulmonary fibrosis. A combination of immunohistochemical, histochemical and in situ hybridization methods will be used to identify cells and expression of specific cytokines by these cells in tissues from diseased and control animals. This overall approach will allow direct assessment of the in vivo role of these cells and combine them with in vitro studies using isolated cells for direct confirmation and more precise and quantitativedelineation of mechanisms.