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。微血管亢进- 通透性导致器官组织水肿，严重低血压导致器官组织低血压。 灌流是脓毒症患者最有害的并发症，导致如此高的死亡率。至 到目前为止，还没有针对败血症的特效疗法。去甲肾上腺素被用作一线血管加压剂以减轻 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在 更高的剂量，会带来不想要的副作用，进一步增加败血症患者的死亡率。大型 大量的液体被注入以扩大血浆容量和改善组织灌注量，但在存在 微血管高通透性增加，这种方法通常会增加组织水肿，并进一步恶化 组织缺氧和损伤。因此，开发安全有效的治疗方法可以减少对 迫切需要液体和血管升压剂来维持血压和足够的组织灌注量。 这一翻译建议的目标是描述微血管高收缩的新机制方面的特征。 耐甲氧西林金黄色葡萄球菌(MRSA)败血症期间的通透性，特别关注相互作用 精氨酸加压素(AVP)V2受体(V2R)与强大的通透性因素(如过量的一氧化氮)之间的关系 氧化物及其代谢物血管生成素-2和缓激肽，并提供有效的治疗选择，以减少 需要液体和去甲肾上腺素，并提高存活率。我们的一般假设是AVP V2R的激活 在脓毒症期间的微血管高通透性及其拮抗剂托伐普坦的使用中起着关键作用， 作为去甲肾上腺素的辅助治疗，可减轻脓毒症所致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液体和血管升压药的需求。为了实现我们的目标 目的：利用临床相关的绵羊MRSA败血症模型，研究以下两个具体目标： 以及对培养的人肺微血管内皮细胞的体外研究。我们特别是 乐观地认为，拟议的研究将导致AVP V2R的翻译临床研究 拮抗剂，作为去甲肾上腺素的辅助治疗，用于感染性休克的治疗。 具体目的1.确定AVP V2R的激活促进微血管病变的严重程度。 MRSA败血症和感染性休克时的通透性和肺水肿。这个目标的目标将是 实现了在活体绵羊和体外培养细胞的研究。 具体目的2.证明AVP V2R拮抗剂作为一种潜在的辅助治疗，对 感染性休克的治疗。通过比较AVP V2R拮抗剂的作用，达到这一目的 托伐普坦加或不加去甲肾上腺素在绵羊MRSA感染性休克模型中的作用 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.