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Τρίτη 31 Οκτωβρίου 2017

NLRP3 Inflammasome Activation Contributes to Mechanical Stretch–Induced Endothelial-Mesenchymal Transition and Pulmonary Fibrosis

Objectives: Mechanical ventilation can induce lung fibrosis. This study aimed to investigate whether ventilator-induced lung fibrosis was associated with endothelial-mesenchymal transition and to uncover the underlying mechanisms. Design: Randomized, controlled animal study and cell culture study. Setting: University research laboratory. Subjects: Adult male Institute of Cancer Research, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) knockout and wild-type mice. Primary cultured mouse lung vascular endothelial cells. Interventions: Institute of Cancer Research, NLRP3 knockout and wild-type mice were subjected to mechanical ventilation (20 mL/kg) for 2 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 24 hours. Measurements and Main Results: Mice subjected to mechanical ventilation exhibited increases in collagen deposition, hydroxyproline and type I collagen contents, and transforming growth factor-β1 in lung tissues. Ventilation-induced lung fibrosis was associated with increased expression of mesenchymal markers (α smooth muscle actin and vimentin), as well as decreased expression of endothelial markers (vascular endothelial–cadherin and CD31). Double immunofluorescence staining showed the colocalization of CD31/α smooth muscle actin, CD31/vimentin, and CD31/fibroblast-specific protein-1 in lung tissues, indicating endothelial-mesenchymal transition formation. Mechanical ventilation also induced NLRP3 inflammasome activation in lung tissues. In vitro direct mechanical stretch of primary mouse lung vascular endothelial cells resulted in similar NLRP3 activation and endothelial-mesenchymal transition formation, which were prevented by NLRP3 knockdown. Furthermore, mechanical stretch–induced endothelial-mesenchymal transition and pulmonary fibrosis were ameliorated in NLRP3-deficient mice as compared to wild-type littermates. Conclusions: Mechanical stretch may promote endothelial-mesenchymal transition and pulmonary fibrosis through a NLRP3-dependent pathway. The inhibition of endothelial-mesenchymal transition by NLRP3 inactivation may be a viable therapeutic strategy against pulmonary fibrosis associated with mechanical ventilation. Drs. Lv, Wang, and Liu contributed equally to this work and should be considered as cofirst authors. Supported, in part, by grants from Shanghai Municipal Commission of Health and Family Planning to Dr. Jiang (No. 2017BR062) and from the National Natural Science Foundation of China to Dr. Jiang (Number 81772117, Number 81571929, Number 81272144), Dr. Zhu (Number 31671213, Number 31271270), Dr. Mao (Number 81372100), and Dr. Liu (Number 81672266, Number 31371164). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Drs. Liu and Zhu received support for article research from the National Natural Science Foundation of China. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Dr. Xiao-Yan Zhu, PhD, Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. E-mail: xiaoyanzhu@smmu.edu.cn; or Dr. Lai Jiang, PhD, Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. E-mail: jianglai@xinhuamed.com.cn Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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