Thurman R G
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365, USA.
Am J Physiol. 1998 Oct;275(4):G605-11. doi: 10.1152/ajpgi.1998.275.4.G605.
It is well known that females show a greater susceptibility to alcohol-induced liver injury than males. Additionally, females who consume alcohol regularly and have been obese for 10 years or more are at greater risk for both hepatitis and cirrhosis. Female rats on an enteral alcohol protocol exhibit injury more quickly than males, with widespread fatty changes over a larger portion of the liver lobule. Levels of plasma endotoxin, intercellular adhesion molecule-1, free radical adducts, infiltrating neutrophils, and nuclear factor-kappaB are increased about twofold more in livers from female than male rats after enteral alcohol treatment. Estrogen treatment in vivo increases the sensitivity of Kupffer cells to endotoxin. Evidence has been presented that Kupffer cells are pivotal in the development of alcohol-induced liver injury. Destruction of Kupffer cells with gadolinium chloride (GdCl3) or reduction of bacterial endotoxin by sterilization of the gut with antibiotics blocks early inflammation due to alcohol. Similar results have been obtained with anti-tumor necrosis factor-alpha antibody. These findings led to the hypothesis that alcohol-induced liver injury involves increases in circulating endotoxin, leading to activation of Kupffer cells, which causes a hypoxia-reoxygenation injury. This idea has been tested using pimonidazole, a nitroimidazole marker, to quantitate hypoxia in downstream pericentral regions of the liver lobule. After chronic enteral alcohol, pimonidazole binding increases twofold. Enteral alcohol also increases free radicals detected with electron spin resonance. Importantly, hepatic hypoxia and radical production detected in bile are decreased by destruction of Kupffer cells with GdCl3. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by alcohol.
众所周知，女性比男性更容易受到酒精性肝损伤的影响。此外，经常饮酒且肥胖10年或更长时间的女性患肝炎和肝硬化的风险更高。采用肠内酒精给药方案的雌性大鼠比雄性大鼠更快出现损伤，肝小叶的更大区域出现广泛的脂肪变性。肠内酒精处理后，雌性大鼠肝脏中的血浆内毒素、细胞间黏附分子-1、自由基加合物、浸润的中性粒细胞和核因子-κB水平比雄性大鼠增加约两倍。体内雌激素治疗会增加库普弗细胞对内毒素的敏感性。有证据表明，库普弗细胞在酒精性肝损伤的发展中起关键作用。用氯化钆（GdCl3）破坏库普弗细胞或用抗生素对肠道进行灭菌以减少细菌内毒素，可阻断酒精引起的早期炎症。使用抗肿瘤坏死因子-α抗体也获得了类似的结果。这些发现导致了一个假设，即酒精性肝损伤涉及循环内毒素增加，导致库普弗细胞活化，进而引起缺氧-复氧损伤。已使用硝基咪唑标记物匹莫硝唑来定量肝小叶下游中央周围区域的缺氧情况，对这一观点进行了验证。慢性肠内酒精给药后，匹莫硝唑结合增加两倍。肠内酒精还会增加用电子自旋共振检测到的自由基。重要的是，用GdCl3破坏库普弗细胞可降低胆汁中检测到的肝脏缺氧和自由基产生。这些数据与库普弗细胞参与酒精所致肝损伤重要性别差异的假设一致。
