ALCOHOL, ACETAMINOPHEN, AND LIVER SINUSOID DYSFUNCTION

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，是一个严重的临床问题在慢性酒精中毒。APAP的毒性反应以出血性小叶中心坏死和血清转氨酶升高为特征，并伴有小叶中心微血管损伤和充血。对这种早期微血管病变的病理生理知之甚少，怀疑它在随后的实质损伤的严重程度进展中很重要。我们建议从这方面研究肝脏对APAP的毒性反应以及酒精对APAP的增强作用。后者是一个日益严重的问题，特别是在大学校园中，但其病理生理学却很少得到实验的关注。初步数据强烈表明，酗酒显著增加肝对APAP损伤的易感性。拟在小鼠中验证的假设是：(a) APAP以剂量依赖的方式引起肝微血管的改变，这种改变先于并增强了实质损伤，酒精增加了肝脏对APAP损伤的易感性；(b)窦状内皮细胞（SEC）及其细胞骨架是微血管损伤的主要部位；(c) SEC损伤与细胞内谷胱甘肽（GSH）和细胞色素P450-2E1 （CYP2E1）以及库普弗细胞和/或募集的炎症细胞释放的介质水平的变化有关。高分辨率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展。光和电子显微镜检查固定标本和分离的SEC将阐明不能在体内可视化的结构变化。这些将与SEC、肝脏和血浆中GSH、CYP2E1、促炎细胞因子、超氧化物、一氧化氮的变化相关，以获得解释显微镜下观察到的反应的线索。抑制这些介质如何改变损伤将进一步阐明它们的作用。这些结果应该为过量使用与自杀企图相关的APAP引起的早期微血管损伤的病理生理学和机制提供新的信息，或者在酒精滥用者中使用治疗剂量的APAP，以及它们对肝损伤的时间过程、进展和程度的贡献。对酒精对肝脏病理生理的影响也应该有更好的认识。

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.