MICROVASCULAR ABNORMALITIES IN SEPSIS

感染性休克是重症监护病房的主要死亡原因， 以血管扩张为特征，周围血管减少 耐药性，这通常对外源性给药难以奏效 血管升压剂。外围设备最重要的决定因素 血管阻力是微动脉阻力的基调，并进行调节 这些小动脉的声调变化是由于局部 血管扩张剂和血管收缩药。涉及到的机制 脓毒症所见的顽固性血管扩张尚未完全阐明。 目前的提案将是第一个调查的研究 一种临床相关的脓毒症模型的微血管异常 阻力小动脉对一系列内源性药物的反应 血管活性物质。 这个项目的长期目标是阐明 患者血管张力异常的病理生理学研究 感染性休克。潜在的假设是低血压和 脓毒症的血流异常分布是由排列紊乱引起的 微血管对内源性血管活性物质的反应。这个 特定的假说是阻力小动脉的反应 用在体视频显微镜测量脓毒症大鼠的发育肌 将不同于对照，而对其机制的解释 血管加压剂反应性的差异将有助于我们理解 重要的致病途径和在创新的发展中 感染性休克的治疗方法。具体目标：1.检验假设 微血管反应性的普遍异常存在于 脓毒症小动脉对内源性血管升压素的反应 化粪池和对照动物。2.评估潜在效应器 脓毒症致血管低反应性机制的检测 第二信使通路抑制物的作用。3.澄清 内源性血管增压剂和血管扩张剂之间的相互作用 检测其对脓毒症患者血管低反应性的影响 一氧化氮合酶、环氧合酶和脂氧合酶抑制剂的作用 脓毒症动物血管加压剂引起的小动脉收缩。4.至 验证细胞因子过量产生一氧化氮的假设- 诱导型一氧化氮合酶在诱导 脓毒症患者的血管低反应性，首先通过比较 选择性和非选择性一氧化氮合酶抑制剂的研究进展 血管加压剂引起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.