Department of Bioengineering, University of Illinois at Chicago (UIC), Chicago, IL 60607, USA.
Department of Pharmacology, University of Illinois at Chicago (UIC), Chicago, IL 60612, USA.
Int J Mol Sci. 2018 Jan 1;19(1):114. doi: 10.3390/ijms19010114.
Mechanical ventilation (MV) performed in respiratory failure patients to maintain lung function leads to ventilator-induced lung injury (VILI). This study investigates the role of sphingolipids and sphingolipid metabolizing enzymes in VILI using a rodent model of VILI and alveolar epithelial cells subjected to cyclic stretch (CS). MV (0 PEEP (Positive End Expiratory Pressure), 30 mL/kg, 4 h) in mice enhanced sphingosine-1-phosphate lyase (S1PL) expression, and ceramide levels, and decreased S1P levels in lung tissue, thereby leading to lung inflammation, injury and apoptosis. Accumulation of S1P in cells is a balance between its synthesis catalyzed by sphingosine kinase (SphK) 1 and 2 and catabolism mediated by S1P phosphatases and S1PL. Thus, the role of S1PL and SphK1 in VILI was investigated using and mice. Partial genetic deletion of protected mice against VILI, whereas deletion of SphK1 accentuated VILI in mice. Alveolar epithelial MLE-12 cells subjected to pathophysiological 18% cyclic stretch (CS) exhibited increased S1PL protein expression and dysregulation of sphingoid bases levels as compared to physiological 5% CS. Pre-treatment of MLE-12 cells with S1PL inhibitor, 4-deoxypyridoxine, attenuated 18% CS-induced barrier dysfunction, minimized cell apoptosis and cytokine secretion. These results suggest that inhibition of S1PL that increases S1P levels may offer protection against VILI.
机械通气（MV）在呼吸衰竭患者中进行以维持肺功能，导致呼吸机引起的肺损伤（VILI）。本研究使用 VILI 啮齿动物模型和肺泡上皮细胞进行循环拉伸（CS），研究鞘脂和鞘脂代谢酶在 VILI 中的作用。MV（0 PEEP（正呼气末压），30 mL/kg，4 h）在小鼠中增强了鞘氨醇-1-磷酸裂解酶（S1PL）的表达和神经酰胺水平，并降低了肺组织中的 S1P 水平，从而导致肺炎症、损伤和细胞凋亡。细胞中 S1P 的积累是其合成由鞘氨醇激酶（SphK）1 和 2 催化和 S1P 磷酸酶和 S1PL 介导的分解代谢之间的平衡。因此，使用 和 小鼠研究了 S1PL 和 SphK1 在 VILI 中的作用。 部分基因缺失 可保护小鼠免受 VILI 影响，而 SphK1 的缺失则加剧了小鼠的 VILI。与生理 5% CS 相比，生理病理 18% CS 下的肺泡上皮 MLE-12 细胞表现出 S1PL 蛋白表达增加和鞘脂碱基水平失调。MLE-12 细胞用 S1PL 抑制剂 4-脱氧吡啶处理可减轻 18% CS 诱导的屏障功能障碍，最小化细胞凋亡和细胞因子分泌。这些结果表明，增加 S1P 水平的 S1PL 抑制可能为 VILI 提供保护。
