ALCOHOL, ACETAMINOPHEN, AND LIVER SINUSOID DYSFUNCTION

由于摄入正常治疗剂量的对乙酰氨基酚(APAP)而导致的急性肝功能衰竭和死亡，泰诺是慢性酒精中毒患者的严重临床问题。APAP的毒性反应以出血性小叶中心坏死和血清转氨酶水平升高为特征，在此之前会出现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学知之甚少，人们怀疑这在随后的实质损伤的严重程度的进展中是重要的。我们建议从这方面研究APAP对肝脏的毒性反应以及酒精对其的增强作用。后者是一个日益严重的问题，特别是在大学校园里，但病理生理学几乎没有得到实验关注。初步数据有力地表明，酗酒显著增加了肝脏对APAP损伤的易感性。将在小鼠身上检验的假说是：(A)APAP以剂量依赖的方式引起肝脏微血管改变，并且这种改变先于并加剧了实质性损伤，并且酒精导致的肝脏对APAP损伤的敏感性增加；(B)肝窦内皮细胞(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)以及Kupffer细胞和/或招募的炎症细胞释放的介质水平的变化有关。高分辨率活体显微镜将被用来确定肝脏微血管功能障碍的动态时空发展。对固定标本和分离的SEC进行光镜和电子显微镜检查，将阐明无法在体内观察到的结构变化。这些变化将与SEC、肝脏和血浆中GSH、CYP2E1、促炎细胞因子、超氧化物歧化酶、一氧化氮的变化相关联，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。这些结果将为过量APAP与自杀未遂或治疗剂量的APAP在酒精滥用者中引起早期微血管损伤的病理生理学和机制提供新的信息，以及它们在肝损伤的时间进程、进展和程度中的作用。对酒精引起的肝脏病理生理学也应该有更好的了解。

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.