KGF and Inhibition of Pulmonary Fibrosis

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Idiopathic pulmonary fibrosis (IPF) is poorly understood, but is felt to involve repeated episodes of lung injury followed by aberrant healing. The interactions between lung epithelial cells and fibroblasts are key determinants of normal healing or the progression of fibrosis. One of the secreted factors that is believed to play a role in the maintenance of lung epithelial integrity is keratinocyte growth factor (KGF) which acts on epithelial cells. Overexpression KGF in the mouse lung provides protection against bleomycin (bleo)-induced lung fibrosis. Our preliminary data indicate that KGF induces expression of the chemokine genes CXCL9, CXCL10 and CXCL11 in the lung that have been previously shown to protect from fibrosis in animal models. KGF treatment of epithelial cells in vitro results in STAT1 phosphorylation that may underlie the increased KGF-induced expression of the specific chemokines. KGF+bleo-treated Tg mice were found to display increased cytoplasmic and nuclear presence of D-catenin in lung epithelial cells. The expression of multiple members of the Wnt/D-catenin signal transduction pathway, was significantly upregulated in the lungs of these mice. We have also observed that KGF prevents the evolution of epithelial cells toward a myofibroblast phenotype. Finally, KGF treatment of lung epithelial cells prevents TGF-D1-mediated downregulation of Id1 protein, a known inhibitor of myogenesis. Based on these data, our hypotheses in this proposal are: 1. Factors induced by KGF in epithelial cells such as CXCL9, CXCL10 and CXCL11 inhibit pulmonary fibrosis. 2. KGF attenuates pulmonary fibrosis by fostering normal epithelial regeneration. 3. KGF antagonizes TGFD- induced signaling mechanisms in epithelial cells that in turn inhibit differentiation towards a fibroblastic phenotype. To test these hypotheses we will: Aim I. Characterize the role of the chemokines CXCL9, CXCL10 and CXCL11, and of IFN-D and STAT1 in KGF-mediated protection from bleo-induced pulmonary fibrosis. Aim II. Characterize the role of Wnt/D-catenin signaling in KGF-mediated inhibition of the effects of TGF-D1 on epithelial cells. Aim III. Characterize the role of inhibitor of differentiation 1 (Id1) molecule in KGF mediated protection from bleomycin induced pulmonary fibrosis.