KGF and Inhibition of Pulmonary Fibrosis

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

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Abstract

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