Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida.
Shock. 2019 Oct;52(4):423-433. doi: 10.1097/SHK.0000000000001280.
Excessive microvascular permeability is a serious complication following hemorrhagic shock and resuscitation (HSR). S1P has been shown to ameliorate microvascular leakage in a model of combined alcohol intoxication and HSR. In the current study, we tested the hypothesis that S1P reduces HSR-induced microvascular leakage by preserving endothelial cell junctional structure and the endothelial glycocalyx through the protection of mitochondrial function. We used an established in vivo rat model of conscious HSR and assessed microvascular leakage, endothelial glycocalyx integrity, and mitochondrial function by intravital microscopy. Junctional integrity in the mesenteric microcirculation was assessed by confocal microscopy. Cultured rat intestinal microvascular endothelial cells monolayers were used to test the ability of S1P to protect against glycocalyx shedding and endothelial barrier dysfunction caused by direct disruption of mitochondrial integrity due to inhibition of mitochondrial complex III. The results show that in vivo, S1P protects against HSR-induced hyperpermeability, preserves the expression of adherens junctional proteins, and protects against glycocalyx degradation. S1P treatment during HSR also protects against mitochondrial membrane depolarization. S1P also protects against mitochondrial dysfunction-induced endothelial barrier dysfunction and glycocalyx degradation by acting through mitochondrial complex III. Taken together, our data indicate that S1P protects against HSR-induced mitochondrial dysfunction in endothelial cells, which in turn improves the structure of the endothelial glycocalyx after HSR and allows for better junctional integrity to the prevention of excess microvascular permeability.
过度的微血管通透性是出血性休克复苏（HSR）后的严重并发症。S1P 已被证明可改善酒精中毒和 HSR 合并模型中的微血管渗漏。在本研究中，我们通过保护线粒体功能来测试 S1P 通过维持内皮细胞连接结构和内皮糖萼来减少 HSR 诱导的微血管渗漏的假设。我们使用了清醒 HSR 的体内大鼠模型，并通过活体显微镜评估了微血管渗漏、内皮糖萼完整性和线粒体功能。通过共聚焦显微镜评估肠系膜微循环中的连接完整性。使用培养的大鼠肠微血管内皮细胞单层来测试 S1P 保护糖萼脱落和内皮屏障功能障碍的能力，内皮屏障功能障碍是由于抑制线粒体复合物 III 导致线粒体完整性直接破坏引起的。结果表明，在体内，S1P 可防止 HSR 引起的高通透性，维持黏附连接蛋白的表达，并防止糖萼降解。HSR 期间的 S1P 治疗也可防止线粒体去极化。S1P 还通过作用于线粒体复合物 III 来防止线粒体功能障碍诱导的内皮屏障功能障碍和糖萼降解。总之，我们的数据表明，S1P 可防止内皮细胞中的 HSR 诱导的线粒体功能障碍，这反过来又改善了 HSR 后的内皮糖萼结构，并允许更好的连接完整性以防止过度的微血管通透性。
