Idiopathic pulmonary fibrosis (IPF) is poorly understood, but is felt to involve repeated episodes of lung injuryfollowed by aberrant healing. The interactions between lung epithelial cells and fibroblasts are keydeterminants of normal healing or the progression of fibrosis. One of the secreted factors that is believed toplay a role in the maintenance of lung epithelial integrity is keratinocyte growth factor (KGF) which acts onepithelial cells. Overexpression KGF in the mouse lung provides protection against bleomycin (bleo)-inducedlung 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 increasedKGF-induced expression of the specific chemokines. KGF+bleo-treated Tg mice were found to displayincreased cytoplasmic and nuclear presence of D-catenin in lung epithelial cells. The expression of multiplemembers of the Wnt/D-catenin signal transduction pathway, was significantly upregulated in the lungs ofthese mice. We have also observed that KGF prevents the evolution of epithelial cells toward a myofibroblastphenotype. Finally, KGF treatment of lung epithelial cells prevents TGF-D1-mediated downregulation of Id1protein, 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 fibroblasticphenotype. To test these hypotheses we will:
Aim I. Characterize the role of the chemokines CXCL9, CXCL10 and CXCL11, and of IFN-D and STAT1 inKGF-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-D1on epithelial cells.
Aim III. Characterize the role of inhibitor of differentiation 1 (Id1) molecule in KGF mediated protection frombleomycin induced pulmonary fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Special Emphasis Panel (ZHL1-CSR-J (M1))
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Children's Hosp Pittsburgh/Upmc Health Sys
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