Frank Reidy Research Center for Bioelectrics (N.B., M.M., P.S., J.D.C.) and School of Medical Diagnostic and Translational Sciences, College of Health Sciences (J.D.C.), Old Dominion University, Norfolk, Virginia; School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana (N.B., M.A.U.); Croston Consulting, San Diego, California (G.E.C.); and Ferring Pharmaceuticals A/S, Copenhagen, Denmark (T.M.R.).
Frank Reidy Research Center for Bioelectrics (N.B., M.M., P.S., J.D.C.) and School of Medical Diagnostic and Translational Sciences, College of Health Sciences (J.D.C.), Old Dominion University, Norfolk, Virginia; School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana (N.B., M.A.U.); Croston Consulting, San Diego, California (G.E.C.); and Ferring Pharmaceuticals A/S, Copenhagen, Denmark (T.M.R.)
J Pharmacol Exp Ther. 2020 Nov;375(2):286-295. doi: 10.1124/jpet.120.000146. Epub 2020 Sep 17.
Sepsis and septic shock are among the most common causes of death in the intensive care unit; advanced therapeutic approaches are thus urgently needed. Vascular hyperpermeability represents a major manifestation of severe sepsis and is responsible for the ensuing organ dysfunction and failure. Vasopressin V receptor (VR) agonists have shown promise in the treatment of sepsis, increasing blood pressure, and reducing vascular hyperpermeability. The effects of the selective VR-selective agonist selepressin have been investigated in an in vitro model of thrombin-, vascular endothelial growth factor-, angiopoietin 2-, and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial hyperpermeability. Results suggest that selepressin counteracts the effects of all four endothelial barrier disruptors in a concentration-dependent manner, as reflected in real-time measurements of vascular permeability by means of transendothelial electrical resistance. Further, selepressin protected the barrier integrity against the LPS-mediated corruption of the endothelial monolayer integrity, as captured by VE-cadherin and actin staining. The protective effects of selepressin were abolished by silencing of the vasopressin VR, as well as by atosiban, an antagonist of the human VR. p53 appears to be involved in mediating these palliative effects, since selepressin strongly induced its expression levels, suppressed the inflammatory RhoA/myosin light chain2 pathway, and triggered the barrier-protective effects of the GTPase Rac1. We conclude that VR-selective agonists, such as selepressin, may prove useful in the improvement of endothelial barrier function in the management of severe sepsis. SIGNIFICANCE STATEMENT: A cardinal sign of sepsis, a serious disease with significant mortality and no specific treatment, is pulmonary endothelial barrier dysfunction that leads to pulmonary edema. Here, we present evidence that in cultured human lung microvascular endothelial cells, the synthetic, selective vasopressin V receptor agonist selepressin protects against endothelial barrier dysfunction caused by four different edemogenic agents, suggesting a potential role of selepressin in the clinical management of sepsis.
脓毒症和感染性休克是重症监护病房中最常见的死亡原因之一；因此，迫切需要先进的治疗方法。血管通透性增加是严重脓毒症的主要表现，也是随后发生的器官功能障碍和衰竭的原因。血管加压素 V 受体 (VR) 激动剂在脓毒症治疗中显示出前景，可升高血压并降低血管通透性。在凝血酶、血管内皮生长因子、血管生成素 2 和脂多糖 (LPS) 诱导的肺微血管内皮通透性增加的体外模型中，已研究了选择性 VR 选择性激动剂 selepressin 的作用。结果表明，selepressin 以浓度依赖的方式对抗所有四种内皮屏障破坏剂的作用，这反映在通过跨内皮电阻实时测量血管通透性。此外，selepressin 保护屏障完整性，防止 LPS 介导的内皮单层完整性破坏，如 VE-钙粘蛋白和肌动蛋白染色所捕获。通过沉默血管加压素 VR 以及拮抗人类 VR 的阿托西班，selepressin 的保护作用被消除。p53 似乎参与介导这些缓解作用，因为 selepressin 强烈诱导其表达水平，抑制炎症性 RhoA/肌球蛋白轻链 2 途径，并触发 GTPase Rac1 的屏障保护作用。我们得出结论，VR 选择性激动剂，如 selepressin，可能在改善严重脓毒症内皮屏障功能方面有用。意义声明：脓毒症的一个主要特征是肺部内皮屏障功能障碍，导致肺水肿，这是一种严重的疾病，死亡率高，没有特定的治疗方法。在这里，我们提供的证据表明，在培养的人肺微血管内皮细胞中，合成的选择性血管加压素 V 受体激动剂 selepressin 可防止四种不同致水肿剂引起的内皮屏障功能障碍，这表明 selepressin 在脓毒症的临床管理中可能具有潜在作用。
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