Department of General Visceral, Vascular and Paediatric Surgery (Department of Surgery I), University of Würzburg, Würzburg, Germany.
Department of Anaesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
Shock. 2018 Jan;49(1):71-81. doi: 10.1097/SHK.0000000000000908.
Endothelial barrier dysfunction is a hallmark in the pathogenesis of sepsis. Sphingosine-1-phosphate (S1P) has been proposed to be critically involved in the maintenance of endothelial barrier function predominately by activating S1P receptor-1 (S1P1). Previous studies have shown that the specific S1P1 agonist SEW2871 improves endothelial barrier function under inflammatory conditions. However, the effectiveness of SEW2871 and potential side effects remained largely unexplored in a clinically relevant model of sepsis. Therefore, this study aimed to evaluate the effects of SEW2871 in the Colon ascendens stent peritonitis (CASP) model.
Polymicrobial sepsis was induced in Sprague-Dawley rats using CASP model that enabled the monitoring of macro-hemodynamic parameters. Twelve hours after surgery, animals received either SEW2871 or sodium chloride. Mesenteric endothelial barrier function was evaluated 24 h after sepsis induction by intravital microscopy. Organ pathology was assessed in lungs. S1P levels, blood gas analyses, and blood values were measured at different time points. In parallel the effect of SEW2871 was evaluated in human dermal microvascular endothelial cells.
In vitro SEW2871 partially stabilized TNF-α-induced endothelial barrier breakdown. However, in vivo SEW2871 caused severe cardiac side effects in septic animals leading to an increased lethality. Sepsis-induced endothelial barrier dysfunction was not attenuated by SEW2871 as revealed by increased FITC-albumin extra-vasation, requirement of intravasal fluid replacement, and pulmonary edema. Interestingly, Sham-operated animals did not present any side effects after SEW2871 treatment.
Our study demonstrates that the application of SEW2871 causes severe cardiac side effects and cannot attenuate the inflammation-induced endothelial barrier breakdown in a clinically relevant sepsis model, suggesting that the time point of administration and the pro-inflammatory milieu play a pivotal role in the therapeutic benefit of SEW2871.
内皮屏障功能障碍是脓毒症发病机制的一个标志。鞘氨醇-1-磷酸（S1P）被认为主要通过激活 S1P 受体-1（S1P1）在维持内皮屏障功能中起关键作用。先前的研究表明，特异性 S1P1 激动剂 SEW2871 在炎症条件下可改善内皮屏障功能。然而，在具有临床相关性的脓毒症模型中，SEW2871 的有效性和潜在的副作用在很大程度上仍未得到探索。因此，本研究旨在评估 SEW2871 在结肠升支支架腹膜炎（CASP）模型中的作用。
使用 CASP 模型在 Sprague-Dawley 大鼠中诱导多微生物脓毒症，该模型可监测宏观血流动力学参数。手术后 12 小时，动物接受 SEW2871 或氯化钠治疗。在脓毒症诱导后 24 小时通过活体显微镜评估肠系膜内皮屏障功能。评估肺部的器官病理学。在不同时间点测量 S1P 水平、血气分析和血液值。同时，评估 SEW2871 在人真皮微血管内皮细胞中的作用。
在体外，SEW2871 部分稳定 TNF-α诱导的内皮屏障破坏。然而，在体内，SEW2871 在脓毒症动物中引起严重的心脏副作用，导致死亡率增加。SEW2871 不能减轻脓毒症诱导的内皮屏障功能障碍，如 FITC-白蛋白外渗增加、需要静脉内补液和肺水肿所揭示的。有趣的是，Sham 手术组动物在接受 SEW2871 治疗后没有出现任何副作用。
本研究表明，SEW2871 的应用会引起严重的心脏副作用，并且不能减轻临床相关脓毒症模型中炎症诱导的内皮屏障破坏，这表明给药时间点和促炎环境在 SEW2871 的治疗效果中起着关键作用。
