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Downregulation of R-Spondin1 Contributes to Mechanical Stretch-Induced Lung Injury

Xu, Chu-Fan PhD1,2; Liu, Yu-Jian PhD2; Wang, Yan MD1; Mao, Yan-Fei PhD1; Xu, Dun-Feng PhD1,2; Dong, Wen-Wen MD1; Zhu, Xiao-Yan PhD3; Jiang, Lai PhD1

doi: 10.1097/CCM.0000000000003767
Online Laboratory Investigation
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Objectives: The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms.

Design: Randomized controlled study.

Setting: University research laboratory.

Subjects: Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells.

Interventions: Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5–4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours.

Measurements and Main Results: R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells.

Conclusions: Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.

1Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

2School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China.

3Department of Physiology, Second Military Medical University, Shanghai, China.

Drs. Xu and Liu contributed equally as co-first authors.

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://journals.lww.com/ccmjournal).

Drs. Xu, Zhu, and Jiang disclosed that this work was supported by grants from Shanghai Municipal Commission of Health and Family Planning to Dr. Jiang (number 2017BR062) and from the National Natural Science Foundation of China (NSFC) to Dr. Jiang (number 81772117, number 81571929), Dr. Zhu (number 31871156, number 31671213), Dr. Mao (number 81772108), and Dr. Liu (number 81672266, number 31371164) and from Doctoral Innovation Fund of Shanghai Jiaotong University School of Medicine for Dr. Xu (number BXJ201828). Dr. Liu received support for article research from NSFC number 81672266. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Xiao-Yan Zhu, PhD, Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai, China. E-mail: xiaoyanzhu@smmu.edu.cn; or Lai Jiang, PhD, Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. E-mail: jianglai@xinhuamed.com.cn

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