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Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis
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A2351 - Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis
Author Block: M. S. Espindola1, D. M. Habiel1, R. Narayanan1, I. Jones1, A. Coelho1, L. Murray2, D. Jiang1, P. W. Noble1, C. M. Hogaboam1; 1Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2MedImmune Ltd, Cambridge, United Kingdom.
Rationale: IPF is characterized by aberrant lung remodeling, which progressively abolishes lung function in a receptor tyrosine kinase (RTK)-dependent manner. Gas6 ligand, Tyro3 and Axl RTK expression and activity is increased in IPF leading us to hypothesize that targeting this RTK pathway would inhibit fibroblast activation and the development of pulmonary fibrosis. Methods: Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/Tyro3, Axl, Mertk (TAM) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of this RTK pathway was also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Results: Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting this pathway with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor, R428, significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents in the same cells. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis humanized SCID/Bg mice. Conclusion: Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF suggesting that targeting this RTK pathway might be an effective anti-fibrotic strategy in this disease.
Author Block: M. S. Espindola1, D. M. Habiel1, R. Narayanan1, I. Jones1, A. Coelho1, L. Murray2, D. Jiang1, P. W. Noble1, C. M. Hogaboam1; 1Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2MedImmune Ltd, Cambridge, United Kingdom.
Rationale: IPF is characterized by aberrant lung remodeling, which progressively abolishes lung function in a receptor tyrosine kinase (RTK)-dependent manner. Gas6 ligand, Tyro3 and Axl RTK expression and activity is increased in IPF leading us to hypothesize that targeting this RTK pathway would inhibit fibroblast activation and the development of pulmonary fibrosis. Methods: Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/Tyro3, Axl, Mertk (TAM) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of this RTK pathway was also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Results: Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting this pathway with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor, R428, significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents in the same cells. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis humanized SCID/Bg mice. Conclusion: Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF suggesting that targeting this RTK pathway might be an effective anti-fibrotic strategy in this disease.
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