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FAK-Related Non-Kinase Attenuates Lung Fibrosis Through Inhibition of Matrix Remodeling
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A2212 - FAK-Related Non-Kinase Attenuates Lung Fibrosis Through Inhibition of Matrix Remodeling
Author Block: P. Che1, L. Yu1, X. Zhao1, G. Cai1, V. J. Thannickal1, M. A. Olman2, Q. Ding1; 1University of Alabama at Birmingham, Birmingham, AL, United States, 2Dept of Pathobiology, Cleveland Clinic, Cleveland, OH, United States.
RATIONALE: We have previously shown that focal adhesion kinase (FAK) plays an important role in cell signaling cascades initiated by cell-matrix interactions. FAK is also a known mechanosensor and activated by matrix remodeling. FAK-related non-kinase (FRNK) negatively regulates fibroblast migration and myofibroblast differentiation. FRNK deficiency leads to increased lung fibrosis in mice in response to bleomycin. FRNK expression is decreased in idiopathic pulmonary fibrosis (IPF). However, the role of FRNK in matrix remodeling during fibrotic reactions has not been studied. This study aims to understand whether FRNK regulates lung fibrosis through modulation of collagen remodeling. METHODS: Primary FRNK deficient lung fibroblasts were derived from FRNK knockout mice. The effect of FRNK deficiency, or FRNK overexpression, on lysyl oxidase (LOX) activity and expression was determined in these fibroblasts treated with or without transforming growth factor beta-1 (TGF-β1), and the findings were compared to that in wild-type lung fibroblasts. Also, tissue transglutaminase (TG) expression was examined in these cells. The in vivo modulation of LOX and TG expression were measured in lung tissues in FRNK deficient and wild type mice challenged with bleomycin. RESULTS: In response to TGF-β1, collagen expression, directed cell migration, and alpha-smooth muscle actin (α-SMA) expression were significantly increased in FRNK deficient lung fibroblasts when compared to that in wild-type lung fibroblasts. FRNK deficiency increases the LOX activity and TG expression and FAK activation. Bleomycin-challenged FRNK deficient mice showed increased LOX activity, TG expression, collagen expression, α-SMA expression, and increased lung fibrosis when compared to that in bleomycin-challenged wild-type mice. Restoration of FRNK expression in FRNK deficient fibroblasts reduced LOX activity, TG expression, and inhibited collagen expression, cell migration and α-SMA expression. CONCLUSIONS: The findings demonstrate that FRNK deficiency enhances the activity of collagen crosslinking proteins and likely contributes to the increased lung fibrosis through modulation of matrix remodeling.
Author Block: P. Che1, L. Yu1, X. Zhao1, G. Cai1, V. J. Thannickal1, M. A. Olman2, Q. Ding1; 1University of Alabama at Birmingham, Birmingham, AL, United States, 2Dept of Pathobiology, Cleveland Clinic, Cleveland, OH, United States.
RATIONALE: We have previously shown that focal adhesion kinase (FAK) plays an important role in cell signaling cascades initiated by cell-matrix interactions. FAK is also a known mechanosensor and activated by matrix remodeling. FAK-related non-kinase (FRNK) negatively regulates fibroblast migration and myofibroblast differentiation. FRNK deficiency leads to increased lung fibrosis in mice in response to bleomycin. FRNK expression is decreased in idiopathic pulmonary fibrosis (IPF). However, the role of FRNK in matrix remodeling during fibrotic reactions has not been studied. This study aims to understand whether FRNK regulates lung fibrosis through modulation of collagen remodeling. METHODS: Primary FRNK deficient lung fibroblasts were derived from FRNK knockout mice. The effect of FRNK deficiency, or FRNK overexpression, on lysyl oxidase (LOX) activity and expression was determined in these fibroblasts treated with or without transforming growth factor beta-1 (TGF-β1), and the findings were compared to that in wild-type lung fibroblasts. Also, tissue transglutaminase (TG) expression was examined in these cells. The in vivo modulation of LOX and TG expression were measured in lung tissues in FRNK deficient and wild type mice challenged with bleomycin. RESULTS: In response to TGF-β1, collagen expression, directed cell migration, and alpha-smooth muscle actin (α-SMA) expression were significantly increased in FRNK deficient lung fibroblasts when compared to that in wild-type lung fibroblasts. FRNK deficiency increases the LOX activity and TG expression and FAK activation. Bleomycin-challenged FRNK deficient mice showed increased LOX activity, TG expression, collagen expression, α-SMA expression, and increased lung fibrosis when compared to that in bleomycin-challenged wild-type mice. Restoration of FRNK expression in FRNK deficient fibroblasts reduced LOX activity, TG expression, and inhibited collagen expression, cell migration and α-SMA expression. CONCLUSIONS: The findings demonstrate that FRNK deficiency enhances the activity of collagen crosslinking proteins and likely contributes to the increased lung fibrosis through modulation of matrix remodeling.
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