ALCOHOL, ACETAMINOPHEN, AND LIVER SINUSOID DYSFUNCTION

酒精、乙酰氨基酚和肝窦功能障碍

• 批准号: 6629507
• 负责人: ROBERT S MCCUSKEY
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629507
• 关键词: Kupffer's cell; acetaminophen; alcoholism /alcohol abuse; chemosensitizing agent; cytochrome P450; drug adverse effect; drug interactions; ethanol; glutathione; histopathology; inflammation; intravital microscopy; laboratory mouse; liver circulation; liver toxic disorder; microcirculation; toxicant interaction

Acute liver failure and death due to the ingestion of normally therapeutic doses of acetaminophen (APAP), Tylenol, is a serious clinical problem in chronic alcoholics. The toxic response to APAP is hallmarked by hemorrhagic centrilobular necrosis and towering levels of serum transaminases which are preceded by centrilobular microvascular injury and congestion. Little is known about the pathophysiology of this early microvascular lesion, which is suspected to be important in the progression of magnitude of the subsequent parenchymal injury. We propose to study this aspect of the toxic response of the liver to APAP and its potentiation by alcohol bringing. The later is a growing and serious problem, especially on college campuses, but is pathophysiology has received little experimental attention. Preliminary data strongly suggests that alcohol binge drinking significantly increases the susceptibility of the liver to injury by APAP. The hypotheses to be tested in mice are: (a) APAP elicits alterations in the hepatic microvascular in a dose dependent manner that precedes and potentiates parenchymal injury and that alcohol bringing increases the susceptibility of the liver to injury by APAP; (b) that sinusoidal endothelial cells (SEC) and their cytoskeleton are the principal sites of microvascular injury; and (c) that injury to SEC is related to changes in their intracellular levels of glutathione (GSH) and cytochrome P450-2E1 (CYP2E1) as well as mediators released from Kupffer cells and/or recruited inflammatory cells. High-resolution in vivo microscopy will be used to determine the dynamic spatial and temporal development of hepatic microvascular dysfunction. Light and electron microscopic examination of fixed specimens and isolated SEC will elucidate structural alterations that can not ve visualized in vivo. These will be correlated with changes in GSH, CYP2E1, pro-inflammatory cytokines, superoxide, nitric oxide in SEC, liver and plasma to gain clues to explain the responses observed microscopically. How inhibition of these mediators modifies the injury will further elucidate their role. The results should provide new information about the pathophysiology and mechanisms involved in the early microvascular injury elicited by overdoses of APAP associated with suicide attempts or therapeutic doses of APAP in abusers of alcohol and their contribution to the time course, progression, and magnitude of hepatic injury. A better knowledge of the hepatic pathophysiology of alcohol bringing also should result.

急性肝衰竭和死亡由于摄入正常治疗剂量的对乙酰氨基酚（APAP），泰诺是慢性酒精中毒的严重临床问题。对APAP的毒性反应以出血性中心坏死和高耸的血清转氨酶水平为标志，在此之前，这些酶的毒性反应是在中心腔微血管损伤和拥塞之前。关于这种早期微血管病变的病理生理学知之甚少，这在随后的实质损伤的幅度进展中很重要。我们建议研究肝脏对APAP的毒性反应的这一方面及其通过酒精带来的增强。后来是一个日益严重的问题，尤其是在大学校园里，但是病理生理学几乎没有引起实验性关注。初步数据强烈表明，酒精暴饮暴食可显着增加肝脏对APAP受伤的敏感性。在小鼠中要测试的假设是：（a）以剂量依赖性方式对肝微血管的APAP引起改变，该方式在实质性损伤之前并增强了实质性损伤，并且酒精会增加肝脏对APAP损伤的易感性； （b）正弦内皮细胞（SEC）及其细胞骨架是微血管损伤的主要部位； （c）SEC的损伤与其细胞内谷胱甘肽（GSH）和细胞色素P450-2E1（CYP2E1）的变化以及从kupffer细胞和/或招募炎性细胞释放的介质有关。高分辨率的体内显微镜将用于确定肝微血管功能障碍的动态空间和时间发育。固定标本和分离的SEC的光和电子显微镜检查将阐明无法在体内可视化的结构变化。这些将与GSH，CYP2E1，促炎性细胞因子，SEC中的超氧化物，肝脏中的一氧化氮，肝脏和血浆中的变化相关，以获得线索以解释显微镜观察到的反应。这些介体的抑制如何改变了伤害将进一步阐明其作用。结果应提供有关早期微血管损伤所涉及的病理生理学和机制的新信息。也应该更好地了解肝脏携带的肝病生理学。