Inhibition of c-Src protects paraquat induced microvascular endothelial injury by modulating caveolin-1 phosphorylation and caveolae mediated transcellular permeability |
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| Institution: | 1. Department of Intensive Care Medicine, The Third People’s Hospital of Chengdu, The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China;2. Department of Respiratory Disease, West China Hospital of Sichuan University, Chengdu, China;1. Baker Heart and Diabetes Institute, Melbourne, Australia;2. Central Clinical School, Monash University, Melbourne, Australia;3. Department of Haematology, The Alfred Hospital, Melbourne, Australia;4. Department of Cardiology, The Alfred Hospital, Melbourne, Australia;1. Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China;2. Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China;1. Department of Occupational Disease, No.4 West China Hospital of Sichuan University, Chengdu, Sichuan, China;2. Center for Occupational Respirology, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China;3. Institute of Biomedical Engineering, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China;3. Divisions of Experimental Surgery and Colorectal Surgery, Taipei Veterans General Hospital, and Department of Medicine, National Yang-Ming University, Taipei 112;4. National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan |
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| Abstract: | The mechanisms underlying paraquat induced acute lung injury (ALI) is still not clear. C-Src plays an important role in the regulation of microvascular endothelial barrier function and the pathogenesis of ALI. In the present study, we found that paraquat induced cell toxicity and an increase of reactive oxygen species (ROS) in endothelium. Paraquat exposure also induced significant increase of caveolin-1 phosphorylation, caveolae trafficking and albumin permeability in endothelial monolayers. C-Src depletion by siRNA significantly attenuate paraquat induced cell toxicity, caveolin-1 phosphorylation, caveolae formation and endothelial hyperpermeability. N-acetylcysteine (NAC) failed to protect endothelial monolayers against paraquat induced toxicity. Thus, our findings suggest that paraquat exposure increases paracellular endothelial permeability by increasing caveolin-1 phosphorylation in a c-Src dependant manner. The depletion of c-Src might protect microvascular endothelial function by regulating caveolin-1 phosphorylation and caveolae trafficking during paraquat exposure, and might have potential therapeutic effects on paraquat induced ALI. |
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| Keywords: | Paraquat Acute lung injury Caveolin-1 Vascular endothelial barrier c-Src |
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