REGULATION OF MATRIX-INDUCED GENES IN LUNG MACROPHAGES

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The hallmarks of chronic inflammation and tissue fibrosis are the influx of inflammatory cells, the accumulation of inflammatory mediators and the increased turnover and production of the extracellular matrix (ECM). There is a growing body of evidence implicating the active role of the ECM in influencing the inflammatory milieu. This proposal is an extension of the applicant's interest in pulmonary inflammation and fibrosis which arose during her three years of basic research, as a fellow, studying the role of the ECM in inflammation. Fragments of the extracellular matrix component hyaluronan (HA), which accumulate in lung inflammation, induce macrophage expression of several chemokines which have been shown to be important mediators of chronic inflammation and fibrosis. Previous research by the applicant revealed that the inflammatory cytokine interferon-gamma (IFN-gamma) exerts a profound effect on HA-induced chemokine gene expression. Specifically, IFN-gamma not only down regulates the gene expression of certain HA-induced pro- fibrotic C-C chemokines but it also synergizes with HA to further induce a subset of anti-fibrotic C-X-C chemokines. The purpose of this proposal is to define the molecular mechanisms by which IFN-gamma regulates HA-induced chemokine expression in alveolar macrophages both in vitro and in vivo. This will be pursued by (1) characterizing the transcriptional mechanisms by which IFN-gamma inhibits MIP-1alpha and MIP-1beta gene expression; (2) characterizing the transcriptional mechanisms by which IFN-gamma synergizes with HA fragments to induce MIG and IP-10 gene expression; and (3) examining the effect of IFN-gamma on lung fibrosis and chemokine production in vivo using the bleomycin model of lung inflammation and fibrosis in an IFN-gamma inducible transgenic mouse system. These studies are to be carried out at the Johns Hopkins University School of Medicine under the sponsorship and guidance of Hyun S. Shin, M.D. who has dedicated over 30 years to the study of macrophage biology. Johns Hopkins provides the supportive and intellectually stimulating environment necessary for the success of this proposal. Although this proposal is based on prior observations made by the applicant, it is a distinctly different line of investigation which focuses on the transcriptional mechanisms of matrix-induced genes in lung macrophages, both in vitro and in vivo. These studies should allow the applicant to further enhance and develop her research skills and enable her to pursue the basic molecular mechanisms of pulmonary fibrosis that might lead to novel treatment approaches.