Interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF) are disabling disorders with fatal outcomes. IPF has a unique constellation of features and an unknown etiology. Research into the pathogenic mechanisms of IPF would be facilitated by an animal model. The homozygous autosomal recessive mutation, motheaten, produces pathologic lung changes resembling IPF in mice which include dense accumulations of macrophages, neutrophils and increased collagen deposition. The mutant mice, but not their normal littermates, have shortened life spans in addition to disregulated monocytopoiesis and mononuclear phagocyte maturation. This model provides the unique opportunity to determine if the abnormal activities of the mononuclear phagocyte compartment previously described by our laboratory contribute to the development of IPF. The interstitial lung disease will be described in detail using quantitative light and electron microscopoic morphometry. The mechanisms responsible165r the localization of motheaten macrophages in the lung tissue will be investigated in vivo using irradiated mice made chimeric with mixtures of marrow cells from motheaten and from CBA T6T6 mice. The role of prostaglandins and leukotrienes as mediators of interstitial pulmonary fibrosis will be determined. The metabolism of archidonic acid along the cyclooxygenase pathway to form prostaglandins and along the lipooxygenase pathway to form leukotrienes by pulmonary alveolar macrophages recovered from the lungs of motheaten and normal littermate mice will be assayed using HPLC chromatography and bioassays. The mechanism of abnormal monocytopoiesis in motheaten mice will be assayed in vitro using the CFU-C assay, including the effects of CSF and prostaglandin-E on progenitor cell proliferation. The proposed experiments will provide the biomedical community with the first comprehensive description of a genetically-determined model of IPF. Defining where the regulation of monocytopoiesis has gone awry will give insight into the process underlying the altered production and performance of the monocyte-macrophage series in inflammatory disease. This information will permit us to view IPF in a new light and devise new innovative strategies for therapy.
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