Impact of Alcohol on Hemorrhagic Shock-Induced Microvascular Dysfunction

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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.