Impact of Alcohol on Hemorrhagic Shock-Induced Microvascular Dysfunction

描述(由申请人提供)：酗酒后的酒精中毒是造成创伤的主要危险因素。尽管复苏策略得到了改进，但美国超过一半的创伤受害者中存在急性酒精中毒，这与创伤和失血性休克的发病率和死亡率更高有关。严重出血的创伤患者加重了肠道缺血再灌注损伤造成的组织损伤，促进了细菌跨肠壁的移位，促进了全身炎症反应。微血管高通透性是全身性炎症的标志，导致肠道和肺部浮肿，损害宿主免受感染的防御，导致进一步威胁生命的并发症。虽然失血性休克导致微血管屏障功能障碍的基本机制已经被剖析，但还没有研究探讨酒精中毒如何进一步加剧失血和复苏过程中的高通透性。因此，更好地抢救和处理醉酒创伤受害者的具体医疗干预措施仍不清楚。这项研究的总体目标是对酒精如何影响微血管功能和微血管对失血性休克的反应有一个基本的了解。中心假说是，急性酒精中毒通过抑制阻力小动脉的肌源性自动调节，导致毛细血管压力和血浆滤过增加，以及通过增加毛细血管后小静脉的细胞旁通透性，促进液体和溶质的外渗，从而加剧失血性休克所致的微血管渗漏，从而导致水肿。相应的目的是1)定量确定酒精中毒如何抑制固有的钙依赖的微动脉对肌源性刺激的反应性，以及2)证明酒精中毒破坏了静脉内皮细胞骨架动力学，增强了失血性休克诱导的微血管高通透性。本研究将结合分子生物学、组织学和活细胞成像技术，利用已建立的急性酒精中毒和失血性休克合并的大鼠模型，研究小动脉反应性和小静脉通透性。这些结果将为酒精中毒在组织、细胞和亚细胞水平进一步破坏出血诱导的微血管病理生理学的机制提供新的见解。这将为转化研究和药物靶向治疗的开发奠定基础，以恢复阻力小动脉和交换小静脉的正常功能，从而更有效地治疗酒精中毒创伤患者。

DESCRIPTION (provided by applicant): Alcohol intoxication following binge alcohol abuse is a major risk factor for traumatic injury. Despite improved resuscitation strategies, acute alcohol intoxication present in more than half of all trauma victims in the United States remains associated with greater morbidity and mortality from traumatic injury and hemorrhagic shock. Trauma victims with severe hemorrhage have aggravated tissue injury from ischemia-reperfusion injury in the gut, facilitating bacterial translocation across the gut wall, promoting a systemic inflammatory response. Microvascular hyperpermeability is hallmark of systemic inflammation, leading to edema in the gut and lungs, compromising host defense from infection, leading to further life-threatening complications. Although the basic mechanisms by which hemorrhagic shock causes microvascular barrier dysfunction have been dissected, no studies have investigated how alcohol intoxication further aggravates hyperpermeability during hemorrhage and resuscitation. Hence, specific medical interventions to better resuscitate and manage the intoxicated trauma victim remain unknown. The overall goal of this study is to develop a fundamental understanding of how alcohol affects microvascular function and the microvascular response to hemorrhagic shock. The central hypothesis is that acute alcohol intoxication exacerbates hemorrhagic shock-induced microvascular leakage by inhibiting myogenic autoregulation in resistance arterioles, causing increased capillary pressure and plasma filtration, and by increasing paracellular permeability of postcapillary venules, facilitating enhanced extravasation of fluids and solutes, causing edema. The corresponding aims are 1) to quantitatively determine how alcohol intoxication inhibits intrinsic, calcium-dependent arteriolar reactivity to myogenic stimuli, and 2) to demonstrate that alcohol intoxication disrupts venular endothelial cytoskeletal dynamics, enhancing hemorrhagic shock-induced microvascular hyperpermeability. This study will utilize an established, well characterized and clinically relevant rat model of combined acute alcohol intoxication and hemorrhagic shock for the investigation of arteriolar reactivity and venular permeability, integrated with molecular biology, histological, and live cell imaging techniques. The results will provide new insights about the mechanisms by which alcohol intoxication further disrupts hemorrhage-induced pathophysiology of the microvasculature at the tissue, cellular, and subcellular level. This will provide the groundwork for translational studies and for development of pharmacological targeted therapies to restore normal function in resistance arterioles and exchange venules, leading to more effective management of alcohol-intoxicated trauma victims.