Upregulation of sphingosine kinase 1 contributes to ventilator-associated lung injury in a two-hit model

Wang,Yan; Gao,Ting‑Ting; Xu,Dun‑Feng; Zhu,Xiao‑Yan; Dong,Wen‑Wen; Lv,Zhou; Liu,Yu‑Jian; Jiang,Lai

doi:10.3892/ijmm.2019.4379

Upregulation of sphingosine kinase 1 contributes to ventilator-associated lung injury in a two-hit model

Authors:
- Yan Wang
- Ting‑Ting Gao
- Dun‑Feng Xu
- Xiao‑Yan Zhu
- Wen‑Wen Dong
- Zhou Lv
- Yu‑Jian Liu
- Lai Jiang
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Affiliations: Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China, Department of Anesthesiology, QILU Children's Hospital of Shandong University, Jinan, Shandong 250022, P.R. China, Department of Physiology, Second Military Medical University, Shanghai 200433, P.R. China, School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, P.R. China
Published online on: October 21, 2019 https://doi.org/10.3892/ijmm.2019.4379
Pages: 2077-2090
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ventilator‑associated lung injury (VALI) remains a significant medical problem in intensive care units. The present study aimed to investigate the role of sphingosine kinase 1 (SPHK1) in VALI using a two‑hit model and explore the potential underlying molecular mechanism. Mice were divided into five groups: i) Non‑ventilated group; ii) non‑ventilated + lipopolysaccharide (LPS) group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + SPHK1 inhibitor group. Mice were administered LPS (1 mg/kg) via an intraperitoneal injection. After 12 h, the mice were anesthetized and connected to a ventilator (10 ml/kg at 150 breaths/min) for 4 h. SPHK1 inhibitor (50 mg/kg) was injected intraperitoneally 1 h prior to ventilation. Mouse lung vascular endothelial cells were treated with LPS and SPHK1 inhibitor, and then subjected to cyclic stretch for 4 h. The present results suggested that the expression of SPHK1 and sphingosine 1 phosphate was upregulated in the two‑hit model of VALI; SPHK1 inhibitor could attenuate VALI in the two‑hit model as observed by hematoxylin and eosin staining, and affected the cell count and the protein content levels in the bronchoalveolar lavage fluid. In addition, treatment with SPHK1 inhibitor reduced the wet‑to‑dry ratio of the lungs and suppressed Evans blue dye leakage into the lung tissue. Furthermore, SPHK1 inhibitor exhibited protective effects on the two‑hit model of VALI by inhibiting the Ras homolog family member a‑mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT‑1) and endothelial hyperpermeability. Additionally, mice were divided into five additional groups: i) Non‑ventilated group; ii) non‑ventilated + LPS group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + Rho‑associated coiled‑coil forming protein kinase (ROCK)1 inhibitor group. ROCK1 inhibitor (10 mg/kg) was injected intraperitoneally 1 h prior to ventilation. The present results suggested that ROCK1 inhibitor could attenuate mechanical stretch‑induced lung endothelial injury and the phosphorylation of MYPT‑1 in vivo and in vitro. Collectively, the present findings indicated that upregulation of SPHK1 may contribute to VALI in a two‑hit model.

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