Fortunato Franco, Deng Xiaoying, Gates Lawrence K, McClain Craig J, Bimmler Daniel, Graf Rolf, Whitcomb David C
University Hospital Zurich, Department of Visceral and Transplantation Surgery, Sternwartstrasse 14, CH-8091 Zurich, Switzerland.
Am J Physiol Gastrointest Liver Physiol. 2006 Feb;290(2):G232-41. doi: 10.1152/ajpgi.00040.2005. Epub 2005 Jun 23.
Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis, and it is likely that a cofactor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and nonalcoholic acute pancreatitis may be influenced by a number of cofactors, including endotoxemia. To explore the effect of a possible cofactor, we used endotoxin [lipopolysaccharide (LPS)] as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected in rats fed an alcohol or control diet and killed 24 h after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We showed that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the downstream apoptosis executor caspase-3 compared with the controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TdT-mediated dUTP nick-end labeling positivity were lower in the alcoholic pancreas injected with LPS, whereas the histopathology and inflammation were more severe compared with the control-fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP to ATP, indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.
已知长期饮酒会增加急性和慢性胰腺炎的易感性，并且可能需要一种辅助因子来启动向酒精性胰腺炎的进展。酒精性和非酒精性急性胰腺炎的严重程度和并发症可能受多种辅助因子影响，包括内毒素血症。为了探究一种可能的辅助因子的作用，我们使用内毒素[脂多糖（LPS）]作为工具来诱导酒精性胰腺中的细胞损伤。向喂食酒精或对照饮食的大鼠单次注射递增剂量的内毒素，并在注射后24小时处死。我们研究了LPS加重酒精喂养大鼠胰腺损伤的机制，以及该损伤是否与细胞凋亡或坏死相关。我们发现，与对照组相比，单独慢性酒精暴露通过内在途径和下游凋亡执行因子半胱天冬酶-3抑制细胞凋亡。在对照和酒精喂养的大鼠中，LPS注射后胰腺坏死和炎症呈剂量依赖性增加，但酒精喂养动物的反应明显更大。注射LPS的酒精性胰腺中半胱天冬酶活性和TdT介导的dUTP缺口末端标记阳性率较低，而与对照喂养动物相比，组织病理学和炎症更严重。对坏死的假定指标二磷酸腺苷与三磷酸腺苷的比率进行评估表明，酒精暴露会加速胰腺对内毒素的坏死反应。这些发现表明，暴露于酒精的胰腺对LPS诱导的损伤更敏感，因为对坏死性细胞死亡而非凋亡性细胞死亡的敏感性增加。与肝脏类似，胰腺在酒精喂养的动物中对LPS的反应更严重，倾向于胰腺坏死而非凋亡。我们推测这种机制可能发生在急性酒精性胰腺炎患者中。
