Etiology of Microvascular Changes in Gram-positive Sepsis: Mechanisms and Therapeutic Options

摘要 感染性休克是重症监护病房最常见的死亡原因。微血管增生- 渗透性导致器官组织水肿，严重低血压导致器官组织低血压， 灌注是脓毒症患者最有害的并发症，导致如此高的死亡率。到 迄今为止，脓毒症尚无特异性治疗方法。去甲肾上腺素被用作第一线血管加压药， 低血压;然而，宿主对去甲肾上腺素的低反应性的发展通常需要其用于 更高的剂量会带来不必要的副作用，进一步增加脓毒症患者的死亡率。大 施用一定量的流体以扩大血浆体积并改善组织灌注，但是，在存在 增加微血管通透性，这种方法往往会增加组织水肿和进一步水肿， 组织缺氧和损伤。因此，开发安全和有效的治疗方法，减少对药物的需求， 迫切需要液体和血管加压剂来维持血压和足够的组织灌注。 这个翻译建议的目标是表征微血管过度的新机制方面， 耐甲氧西林金黄色葡萄球菌（MRSA）脓毒症期间的通透性，特别关注相互作用 精氨酸加压素（AVP）V2受体（V2 R）和有效的渗透性因子，如过量的一氧化氮， 氧化物及其代谢产物血管生成素-2和缓激肽，并提供有效的治疗选择， 需要液体和去甲肾上腺素，并提高生存率。我们的假设是AVP V2 R的激活 在脓毒症和其拮抗剂托伐普坦的使用过程中的微血管通透性过高中起关键作用， 作为去甲肾上腺素的辅助治疗将减轻脓毒症引起的多器官功能障碍的严重程度。我们 进一步假设托伐普坦将有效地减少流体和血管加压剂的需求。实现我们 目的，我们建议研究以下两个具体目标，使用临床相关的MRSA脓毒症绵羊模型， 以及用培养的人肺微血管内皮细胞进行的体外研究。我们特别 乐观地认为，拟议的研究将导致AVP V2 R的转化临床研究的可能性 拮抗剂，作为去甲肾上腺素的辅助治疗，用于管理脓毒性休克。 具体目标1。为了确定AVP V2 R的激活促进微血管高血压的严重程度， 在MRSA脓毒症和脓毒性休克期间的渗透性和肺水肿。这一目标的目标将是 实现了在绵羊体内和体外培养细胞研究。 具体目标2。证明AVP V2 R拮抗剂作为潜在的辅助治疗， 感染性休克的治疗通过比较AVP V2 R拮抗剂的作用， 托伐普坦联合或不联合去甲肾上腺素在MRSA感染性休克绵羊模型中的应用，特别强调 心血管衰竭

Abstract Septic shock is the most frequent cause of death in the intensive care units. The microvascular hyper- permeability resulting in organ tissue edema and the severe hypotension resulting in organ tissue hypo- perfusion are the most detrimental complications of septic patients leading to such a high mortality rate. To date, there are no specific therapies for sepsis. Norepinephrine is used as a first line vasopressor to attenuate hypotension; however, development of host hypo-responsiveness to norepinephrine often requires its use in higher doses, that bring with them unwanted side effects that further increase mortality of septic patients. Large amount of fluids is administered to expand plasma volume and improve tissue perfusion, but, in presences of increased microvascular hyper-permeability, this approach often augments tissue edema and further worsens the tissue hypoxia and injury. Thus, development of safe and efficient therapy that reduces the requirement for both fluid and vasopressors to maintain blood pressure and adequate tissue perfusion is in urgent need. The goal of this translational proposal is to characterize novel mechanistic aspects of microvascular hyper- permeability during methicillin-resistant Staphylococcus aureus (MRSA) sepsis, with special focus on interplay between arginine vasopressin (AVP) V2 receptor (V2R) and potent permeability factors, such as excessive nitric oxide and its metabolites, angiopoieitin-2, and bradykinin and offer efficient therapeutic option that reduces the need for fluid and norepinephrine, and improves survival. Our general hypothesis is that activation of AVP V2R plays a critical role in microvascular hyper-permeability during sepsis and the use of its antagonist tolvaptan, as an adjunct therapy to norepinephrine will alleviate severity of sepsis-induced multi-organ dysfunctions. We further hypothesize that tolvaptan will effectively reduce fluid and vasopressor requirements. To achieve our goal, we propose to study following two specific aims, using clinically relevant ovine model of MRSA sepsis as well as in vitro studies with cultured human pulmonary microvascular endothelial cells. We are particularly optimistic about the possibility that the proposed research will lead to translational clinical studies for AVP V2R antagonists, as an adjunct therapy to norepinephrine, for management of septic shock. Specific Aim 1. To determine that activation of AVP V2R promotes severity of microvascular hyper- permeability and pulmonary edema during MRSA sepsis and septic shock. The goal of this aim will be achieved performing both in vivo ovine and in vitro cultured cell studies. Specific Aim 2. To demonstrate safety and efficacy AVP V2R antagonist, as a potential adjunct therapy, for treatment of septic shock. The goal of this aim will be achieved comparing effects of AVP V2R antagonist tolvaptan with or without norepinephrine in ovine model of MRSA septic shock with special emphasis on cardiovascular collapse.