ETHANOL RESULTS IN OXIDANT DEPENDENT TISSUE INJURY

描述：（改编自研究者摘要）慢性酒精中毒 是美国的一个主要健康问题， 每年的医疗费用。 酒精引起的肝损伤 造成了大多数的发病率和死亡率， 长期饮酒 肝硬化是第六常见的 在美国的死因，酒精是导致 41 - 95%的病例中存在病原体。 疾病的发展从 脂肪浸润和炎症到不可逆的组织损伤， 肝移植是唯一的选择 虽然慢性 饮酒主要导致肝功能障碍，也有 与血管（中风、高血压）和肺（急性 呼吸窘迫综合征）并发症。 慢性酒精刺激 与活性氧和氮的产生有关 物种和受损的抗氧化防御系统。 但没有 系统整合慢性乙醇影响的研究 消耗到反应性自由基物种的产生， 嘌呤，蛋白质和脂质，以及随之而来的肝脏， 肺和血管结构/功能。 研究人员假设 长期服用乙醇会增加一氧化氮（NO）、超氧化物 (02-)和过氧亚硝酸盐（ONOO-）的生产，从而导致硝化和 生物分子的氧化和受损的组织结构/功能。 他们 建议利用遗传定义的小鼠模型来调节氧化剂 产生酶（iNOS和AO/XO）和抗氧化防御（CuZn SOD 1）， 获得对乙醇诱导的生物分子硝化的机理洞察 以及血管和组织结构/功能的改变。 的 研究人员将最终应用有针对性的药物干预 以减少酒精引起的损伤 具体目标：1。 定义 NO、O2-和ONOO-在生物分子（嘌呤， 蛋白质和脂质）以及受损的组织和血管结构/功能 慢性乙醇给药后 2. 调节NO和O2- 生产，以（a）揭示对肝，肺和 血管系统，和（B）减弱组织和血管功能障碍相关 慢性酒精消耗。 3. 利用靶向药理学 最大限度地减少慢性乙醇诱导的生物分子硝化的干预措施 （嘌呤，蛋白质和脂质）和随后的组织损伤， 血管结构/功能。这些观察结果将为 理解这些相互作用， 超氧阴离子与一氧化氮在肝、肺、血管组织损伤中作用 长期服用乙醇引起的。 获得的机械学见解 这些研究将指导药物干预的发展， 限制活性物质的有害影响并降低发病率 和死亡率与慢性酒精消费，并作为一个 人类临床试验的前奏

DESCRIPTION: (Adapted from the Investigator's Abstract) Chronic alcoholism is a major health problem in the U.S. resulting in over $12 billion dollars in medical expenses each year. Alcohol-induced hepatic damage is responsible for the majority of the morbidity and mortality associated with chronic alcohol consumption. Liver cirrhosis ranks as the 6th most common cause of death in the U.S., with ethanol implicated as the causative etiologic agent in 41-95 percent of the cases. The disease progresses from fatty infiltration and inflammation to irreversible tissue damage, with liver transplantation ultimately the only recourse. Although chronic alcohol consumption results primarily in hepatic dysfunction, there are also strong links to vascular (stroke, hypertension) and pulmonary (acute respiratory distress syndrome) complications. Chronic ethanol consumption has been linked to increased production of reactive oxygen and nitrogen species and compromised antioxidant defense systems. However, there are no studies which systematically integrate the effects of chronic ethanol consumption to the generation of reactive radical species, nitration of purines, proteins and lipids, and the consequent alterations in hepatic, pulmonary, and vascular structure/function. The investigators hypothesize that chronic ethanol administration increases nitric oxide ( NO), superoxide (02-), and peroxynitrite (ONOO-) production, thus leading to nitration and oxidation of biomolecules and compromised tissue structure/function. They propose to utilize genetically defined mouse models to modulate oxidant generating enzymes (iNOS and AO/XO) and antioxidant defenses (CuZn SOD1) to gain mechanistic insight into the ethanol-induced nitration of biomolecules and alterations in vascular and tissue structure/function. The investigators will ultimately apply targeted pharmacological interventions to minimize the ethanol-induced injury. Specific Aims: 1. Define the contribution of NO, O2-, and ONOO- in nitration of biomolecules (purines, proteins and lipids) and impaired tissue and vascular structure/function following chronic ethanol administration. 2. Modulate NO and 02- production to (a) reveal mechanisms of oxidative injury to liver, lung and vasculature, and (b) attenuate tissue and vascular dysfunction associated with chronic ethanol consumption. 3. Utilize targeted pharmacologic interventions to minimize chronic ethanol-induced nitration of biomolecules (purine, protein, and lipid) and subsequent impairment of tissue and vascular structure/function.These observations will provide a foundation for understanding the interactions for understanding the interactions of superoxide with NO in hepatic, pulmonary, and vascular tissue injury resulting from chronic ethanol administration. Mechanistic insights gained from these studies will guide development of pharmacologic interventions to limit the detrimental effects of reactive species and decrease the morbidity and mortality associated with chronic alcohol consumption and serve as a prelude to human clinical trials.