Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA; Department of Surgery, University of Texas Medical Branch Galveston, TX, USA.
Pharmacol Res. 2021 Jan;163:105272. doi: 10.1016/j.phrs.2020.105272. Epub 2020 Nov 4.
Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (VR). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (VR) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of VR activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved VR antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with VR agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the VR-induced increase in permeability is mediated by phospholipase C beta (PLCβ) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-VR axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.
耐甲氧西林金黄色葡萄球菌（MRSA）脓毒症是一种与血管渗漏和预后不良相关的严重病症。脓毒症的血流动力学管理以低血压为目标，但目前尚无针对血管渗漏的特定治疗方法。精氨酸加压素（AVP）已在脓毒症中用于通过激活 AVP 受体 1（VR）来促进血管收缩。然而，最近的证据表明，液体潴留的增加可能与 AVP 受体 2（VR）的激活有关，从而使脓毒症的预后恶化。因此，我们假设抑制 VR 激活可改善脓毒症期间微血管高通透性的严重程度。该假说使用了一种经过充分验证且具有临床相关性的绵羊耐甲氧西林金黄色葡萄球菌肺炎/脓毒症模型和人肺微血管内皮细胞（HMVEC）的体外检测进行了测试。体内实验表明，用托伐普坦（TLVP）治疗脓毒症绵羊，TLVP 是一种获得 FDA 批准的 VR 拮抗剂，可显著减轻脓毒症引起的液体潴留，并显著降低肺含水量。这些病理变化不受 VR 激动剂去氨加压素（DDAVP）治疗的影响。此外，用 DDAVP 和 DDAVP 加耐甲氧西林金黄色葡萄球菌孵育培养的 HMVEC，会显著增加细胞旁通透性。最后，TLVP 显著减轻了 DDAVP 和耐甲氧西林金黄色葡萄球菌诱导的高通透性。随后的蛋白质和基因表达测定确定，VR 诱导的通透性增加是由磷脂酶 Cβ（PLCβ）和强效通透性因子血管生成素-2 介导的。总之，我们的研究结果表明，AVP-VR 轴的激活在革兰氏阳性菌脓毒症严重微血管高通透性的病理生理学中起着关键作用。应考虑将拮抗剂 TLVP 作为脓毒症患者的辅助治疗。这项具有临床相关性的动物研究的结果对临床实践具有高度的转化意义。
