ALCOHOL, ACETAMINOPHEN, AND LIVER SINUSOID DYSFUNCTION

由于摄入正常治疗剂量的对乙酰氨基酚（APAP），泰诺，导致急性肝功能衰竭和死亡，是慢性酒精中毒者的严重临床问题。对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标志，而这是在小叶中心微血管损伤和充血之前发生的。关于这种早期微血管病变的病理生理学知之甚少，怀疑其在随后的实质损伤程度的进展中是重要的。我们建议研究这方面的毒性反应的肝脏APAP及其增强酒精带来的。后者是一个日益严重的问题，特别是在大学校园，但病理生理学很少受到实验的关注。初步数据强烈表明，酗酒显着增加肝脏对APAP损伤的敏感性。在小鼠中检验的假设是：（a）APAP以剂量依赖的方式诱发肝微血管的改变，这种改变先于并加强实质损伤，酒精使肝脏对APAP损伤的敏感性增加;（B）窦状隙内皮细胞（SEC）及其细胞骨架是微血管损伤的主要部位;和（c）SEC的损伤与其细胞内谷胱甘肽（GSH）和细胞色素P450- 2 E1（CYP 2 E1）水平以及枯否细胞和/或募集的炎性细胞释放的介质的变化有关。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。固定标本和分离SEC的光镜和电镜检查将阐明体内无法观察到的结构变化。这些将与SEC、肝脏和血浆中GSH、CYP 2 E1、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。如何抑制这些介质修改损伤将进一步阐明他们的作用。这些结果应该提供新的信息的病理生理学和机制所涉及的早期微血管损伤引起过量的APAP与自杀企图或治疗剂量的APAP在酒精滥用者和他们的贡献的时间过程中，进展和肝损伤的程度。更好地了解酒精带来的肝脏病理生理学也应该导致。

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.