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A5791 - Molecular Regulation of Survival Pathways in Multiple Mesenchymal Cells
Author Block: R. Kasam1, G. B. Reddy2, A. G. Jegga3, S. K. Madala4; 1Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, 2National Institute of Nutrition, Hyderabad, India, 3Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, United States, 4Pulm Med, Cincinnati Children's Hosp, Cincinnati, OH, United States.
Rationale: Apoptotic clearance of mesenchymal cells is critical for a normal wound healing in response to injury in the lung. Whereas, increased mesenchymal cell survival or resistance to apoptosis is responsible for impaired wound healing and progressive fibrosis in the lung. However, is not understood well. Here we assessed molecular regulators of apoptosis in fibrocytes and fibroblasts from IPF and mouse model of TGFα-induced pulmonary fibrosis. Methods: To identify molecular regulators of survival pathways, we compared gene expression profiles from IPF and mouse model of TGFα-induced pulmonary fibrosis. Genes involved in resistance to apoptosis were validated in the lungs and mesenchymal cells using RT-PCR. The apoptosis of fibrocytes and fibroblasts was assessed by measuring caspase 3/7 activity using Incucyte ZOOM real-time kinetic system. Results: Global gene expression and quantitative RT-PCR analysis of the lungs revealed that the genes involved in the resistance to apoptosis are markedly induced in IPF and mouse model of TGFα-induced pulmonary fibrosis. Importantly, lung resident fibroblasts and fibrocytes isolated from fibrotic lungs display resistance to Fas-induced apoptosis compared to normal cells. Furthermore, gene networks of apoptosis are similarly dysregulated in both fibrocytes and fibroblasts. Pro-Apoptotic genes such as Fas, Bak, Bim, and Bid are downregulated, while anti-apoptotic genes such as Bcl-2 and Bcl-xL are upregulated in apoptosis resistant fibrocytes and fibroblasts. Summary: Our findings indicate for the first time that fibrocytes have elevated expression of survival pathway genes and resistance to apoptotic clearance. Importantly, extrinsic and intrinsic apoptosis pathways are similarly dysregulated in fibrocytes and fibroblasts. Our findings also demonstrate a molecular mimicry in mesenchymal cell survival pathways between IPF and TGFα model.