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Laminin Alpha1 Is a Genetic Modifier of TGF-beta1-Stimulated Pulmonary Fibrosis
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A3677 - Laminin Alpha1 Is a Genetic Modifier of TGF-beta1-Stimulated Pulmonary Fibrosis
Author Block: C. Lee1, S. Cho2, W. Cho3, J. Park1, A. M. Choi4, I. O. Rosas5, M. Zheng6, G. Peltz6, C. Lee1, J. A. Elias1; 1Brown University, Providence, RI, United States, 2Weill Cornell Medical Center, New York, NY, United States, 3Asan School of Medicine, Seoul, Korea, Republic of, 4Weill Cornell Medical College, New York, NY, United States, 5Brigham Womens Hosp, Boston, MA, United States, 6Stanford University, Palo Alto, CA, United States.
Background Idiopathic pulmonary fibrosis (IPF) is a complex and progressive lung disease with significant morbidity and mortality. However, underlying mechanism(s) or genetic factors regulating pulmonary fibrosis have not been fully understood. In this study, transgenic overexpression of profibrotic cytokine TGF-β in the lung induced variable levels of pulmonary fibrosis depending on the background strains of mice, suggesting potential genetic control of pulmonary fibrosis.Hypothesis We hypothesized that genetic factor(s) are implicated in controlling fibrotic tissue response in the lungs of TGF-β Tg mice.Methods To define this genetic factor, we performed in silico haplotype analysis and mRNA profiling analysis on 10 genetic background strains of mice and identified laminin-α1(Lama1) as a candidate gene. Subsequent in vivo and in vitro evaluation validate a significant role of Lama1 in the pathogenesis of TGF-β and bleomycin-stimulated pulmonary fibrosis. Results. Our studies demonstrated that Lama1 is prominently induced by TGF-β stimulation mainly in the macrophages and fibroblasts in the lung and siRNA silencing of Lama1 significantly reduced TGF-β-stimulated pulmonary fibrosis. In vitro studies using alveolar macrophages and fibroblasts also demonstrated that Lama1 plays an important role in alternative and fibrotic macrophage activation and TGF-β-stimulated fibroblast proliferation, myofibroblast transformation. In accordance with these murine findings, a significant increase of Lama1 expression in the lungs from the patients with IPF was noted compared to controls Conclusion These studies demonstrated that Lama1 is a genetic modifier of TGF-β-stimulated pulmonary fibrosis. They also suggest that a potential use of Lama1 as a biomarker and therapeutic target of pulmonary fibrosis in which TGF-β plays an essential role.
Author Block: C. Lee1, S. Cho2, W. Cho3, J. Park1, A. M. Choi4, I. O. Rosas5, M. Zheng6, G. Peltz6, C. Lee1, J. A. Elias1; 1Brown University, Providence, RI, United States, 2Weill Cornell Medical Center, New York, NY, United States, 3Asan School of Medicine, Seoul, Korea, Republic of, 4Weill Cornell Medical College, New York, NY, United States, 5Brigham Womens Hosp, Boston, MA, United States, 6Stanford University, Palo Alto, CA, United States.
Background Idiopathic pulmonary fibrosis (IPF) is a complex and progressive lung disease with significant morbidity and mortality. However, underlying mechanism(s) or genetic factors regulating pulmonary fibrosis have not been fully understood. In this study, transgenic overexpression of profibrotic cytokine TGF-β in the lung induced variable levels of pulmonary fibrosis depending on the background strains of mice, suggesting potential genetic control of pulmonary fibrosis.Hypothesis We hypothesized that genetic factor(s) are implicated in controlling fibrotic tissue response in the lungs of TGF-β Tg mice.Methods To define this genetic factor, we performed in silico haplotype analysis and mRNA profiling analysis on 10 genetic background strains of mice and identified laminin-α1(Lama1) as a candidate gene. Subsequent in vivo and in vitro evaluation validate a significant role of Lama1 in the pathogenesis of TGF-β and bleomycin-stimulated pulmonary fibrosis. Results. Our studies demonstrated that Lama1 is prominently induced by TGF-β stimulation mainly in the macrophages and fibroblasts in the lung and siRNA silencing of Lama1 significantly reduced TGF-β-stimulated pulmonary fibrosis. In vitro studies using alveolar macrophages and fibroblasts also demonstrated that Lama1 plays an important role in alternative and fibrotic macrophage activation and TGF-β-stimulated fibroblast proliferation, myofibroblast transformation. In accordance with these murine findings, a significant increase of Lama1 expression in the lungs from the patients with IPF was noted compared to controls Conclusion These studies demonstrated that Lama1 is a genetic modifier of TGF-β-stimulated pulmonary fibrosis. They also suggest that a potential use of Lama1 as a biomarker and therapeutic target of pulmonary fibrosis in which TGF-β plays an essential role.
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