MICROVASCULAR ABNORMALITIES IN SEPSIS

脓毒性休克是重症监护病房的主要死亡原因， 以血管舒张为特征，外周血管减少 耐药性，这往往是难治性外源性给药 血管加压剂。 最重要的决定性因素是 血管阻力是阻力小动脉的张力， 这些小动脉中张力的变化是由局部 血管扩张剂和血管收缩剂。 参与的机制 脓毒症中出现的难治性血管舒张尚未完全阐明。 目前的建议将是第一个研究调查 临床相关脓毒症模型中的微血管异常 测试阻力小动脉对一系列内源性 血管活性物质 本项目的长期目标是阐明 在患者中观察到的血管张力异常的病理生理学 感染性休克 潜在的假设是低血压和 脓毒症血流分布异常是由紊乱引起的 在微血管对内源性血管活性物质的反应中。 的 具体假设是， 利用活体视频显微镜测量脓毒症大鼠的提睾肌 将与对照不同，并且阐明 血管加压素反应性的差异将有助于我们理解 重要的致病途径和创新的发展， 治疗感染性休克 具体目标：1.为了检验这一假设 微血管反应性的普遍异常存在于 脓毒症的小动脉对内源性血管加压素的反应， 败血症和对照动物。 2.评价潜在效应物 脓毒症引起的血管低反应性的机制，通过测量 第二信使通路抑制剂的作用。 3.阐明 内源性血管升压药和血管舒张药之间的相互作用 通过测试其作用来介导脓毒症中的血管低反应性 一氧化氮合酶、环氧合酶和脂氧合酶抑制剂对 脓毒症动物中血管加压素诱导的小动脉收缩。4.到 检验细胞因子导致一氧化氮过量的假设 诱导型一氧化氮合酶在诱导 脓毒症中的血管低反应性，首先通过比较 选择性和非选择性一氧化氮合酶抑制剂 血管加压素诱导的脓毒症动物的小动脉收缩，然后 通过测量转基因败血症动物的血管反应性， 缺乏诱导型一氧化氮合酶。

Septic shock, the leading cause of death in intensive care units, is characterized by vasodilation with decreased peripheral vascular resistance, which is often refractory to exogenously administered vasopressor agents. The most important determinant of peripheral vascular resistance is the tone of resistance arterioles, and modulation of tone in these arterioles results from a complex interplay of local vasodilators and vasoconstrictors. The mechanisms involved in the refractory vasodilation seen in sepsis have not been fully elucidated. The current proposal would be the first study to investigate microvascular abnormalities in a clinically relevant model of sepsis by testing responses of resistance arterioles to a range of endogenous vasoactive substances. The long-term objective of this project is to elucidate the pathophysiology of the abnormalities in vascular tone seen in patients with septic shock. The underlying hypothesis is that hypotension and abnormal distribution of blood flow in sepsis result from derangements in microvascular responses to endogenous vasoactive substances. The specific hypothesis is that responses of resistance arterioles in cremaster muscles of septic rats measured using in vivo videomicroscopy will differ from controls, and that elucidation of the mechanisms of differences in vasopressor responsiveness will aid in our understanding of important pathogenetic pathways and in the development of innovative therapies for septic shock. Specific aims: 1. To test the hypothesis that a general abnormality of microvascular reactivity is present in sepsis by comparing arteriolar responses to endogenous vasopressors in septic and control animals. 2. To evaluate potential effector mechanisms of sepsis-induced vascular hyporesponsiveness by measuring the effects of inhibitors of second messenger pathways. 3. To elucidate interactions between endogenous vasopressors and vasodilators in mediating vascular hyporesponsiveness in sepsis by testing the effects of nitric oxide synthase, cyclooxygenase, and lipoxgenase inhibitors on vasopressor-induced arteriolar constriction in septic animals. 4. To test the hypothesis that overproduction of nitric oxide by cytokine- inducible nitric oxide synthase plays a pivotal role in inducing vascular hyporesponsiveness in sepsis, first by comparing the effects of selective and nonselective nitric oxide synthase inhibitors on vasopressor-induced arteriolar constriction in septic animals, and then by measuring vascular responsiveness in transgenic septic animal deficient in inducible nitric oxide synthase.