Mechanisms and Meanings of Impaired Microvascular Responses in Human Sepsis

描述（由申请方提供）：严重脓毒症是对感染的全身反应，最终导致急性器官衰竭。脓毒症的临床前模型表明，以低反应血管和不均匀血流为特征的微血管系统紊乱导致器官衰竭。然而，这些发现转化为成功的人类疗法受到动物模型和人类脓毒症之间的差异的影响。新的微血管成像技术为研究脓毒症复苏的潜在治疗靶点提供了新的机会。肾素-血管紧张素系统（RAS）和精氨酸加压素（AVP）系统代表了在人类脓毒症中经历微血管影响的变化的两个反应系统。这些系统之间存在显著的相互作用，两者都可以在治疗上进行操纵。因此，RAS和AVP似乎都是复苏的重要靶点。我们假设血管收缩活性导致微血管系统中的不均匀血流和对缺血的反应受损，最终导致人类败血症中的器官衰竭和死亡。为了研究这一假设，我们提出了三个具体目标。1)确定对缺血的微血管反应受损是否与人类败血症中的异质性微血管流量和死亡率相关。我们将使用近红外光谱（NIRS）来测量微血管对缺血的反应，并通过舌下毛细血管分析来加强我们的发现。因此，我们将在一项研究中确定不同组织的微血管功能，以确定这些指标是否与死亡率相关。我们将确定哪些血管收缩剂与微血管变化最密切相关。2)确定AVP输注对人脓毒症期间RAS激活和微血管功能的影响。患者将接受AVP或生理盐水，我们将比较微血管功能和RAS激活。我们将确定微血管流量和反应性的诱导变化是否与RAS激活的变化一致。3)研究RAS作为人类脓毒症微血管复苏的潜在靶点。我们将抑制败血症受试者局部微循环中的RAS，从而测试RAS是否有助于对缺血的微血管反应受损。通过在血管调节的临床研究方面具有专业知识的重症监护医师-研究者和医师-科学家之间的合作，我们提出了与患者结局相关的研究，并阐明了导致人类脓毒症微血管功能障碍的重要机制。

DESCRIPTION (provided by applicant): Severe sepsis is a systemic response to infection that culminates in acute organ failure. Preclinical models of sepsis demonstrate that a disturbed microvasculature characterized by hyporesponsive vessels and heterogeneous flow contributes to organ failure. However, translation of these findings into successful human therapies is impaired by discrepancies between animal models and human sepsis. Novel microvascular imaging provides new opportunities to study potential therapeutic targets of resuscitation in human sepsis. The renin- angiotensin system (RAS) and arginine vasopressin (AVP) system represent two response systems that undergo changes with microvascular implications in human sepsis. There are significant interactions between these systems, and both can be manipulated therapeutically. Thus both RAS and AVP appear to be important targets for resuscitation. We hypothesize that vasoconstrictor activity contributes to heterogeneous blood flow and impaired responses to ischemia in the microvasculature that culminate in organ failure and death in human sepsis. To investigate this hypothesis we have developed three specific aims. 1) Determine if impaired microvascular responses to ischemia are related to heterogeneous microvascular flow and mortality in human sepsis. We will use Near Infrared Spectroscopy (NIRS) to measure microvascular responses to ischemia, and strengthen our findings with sublingual capillary analysis. We will therefore determine microvascular function in diverse tissues in a study powered to determine if these measures are associated with mortality. We will determine which vasoconstrictors are most closely related to microvascular changes. 2) Determine the effects of AVP infusions upon RAS activation and microvascular function during human sepsis. Patients will receive either AVP or saline, and we will compare microvascular function and RAS activation. We will determine if induced changes in microvascular flow and responsiveness are consistent with changes in RAS activation. 3) Investigate RAS as a potential target of microvascular resuscitation in human sepsis. We will inhibit RAS in the regional microcirculation of septic subjects, thereby testing if RAS contributes to impaired microvascular responses to ischemia. Through collaboration between an intensivist- investigator and a physician-scientist with expertise in clinical studies of vascular regulation, we propose studies that will be pertinent to patient outcomes and elucidate important mechanisms that contribute to microvascular dysfunction in human sepsis.