Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Germany.
Autophagy. 2009 Aug;5(6):850-3. doi: 10.4161/auto.8839. Epub 2009 Aug 23.
In contrast to apoptosis, necrosis is generally viewed as a pro-inflammatory cell death mechanism. Accumulation of autophagosomes and massive acinar cell necrosis is observed in human acute pancreatitis, a severe and potentially lethal inflammatory condition. We have investigated the incidence of apoptosis, autophagy and necrosis affecting acinar cells in a rat model of acute pancreatitis induced by chronic alcohol intake and acute endotoxemia. We have observed that the combination of alcohol exposure and endotoxemia results in substantial accumulation of autophagosomes without an increase in autolysosomes, coupled to the depletion of LAMP-2, a lysosomal protein required for the proper fusion of autophagosomes with lysosomes. Alcohol plus endotoxemia favors the switch from apoptotic to necrotic cell death, as indicated by histopathological examination, reduced ATP levels, suppressed caspase activation, as well as the nuclear release of the proinflammatory factor HMGB1. Importantly, patients with alcoholic pancreatitis also exhibit local LAMP-2 depletion, recapitulating the results obtained in the animal model. We suggest that acinar cell vacuolization in pancreatitis is mediated by an endotoxemia-induced depletion of LAMP-2, which in turn facilitates the accumulation of autophagosomes due to the deficient formation of autolysosomes. Hence, we postulate that the depletion of lysosomal proteins may play a critical role in the pathogenesis of acute pancreatitis.
与细胞凋亡相反，细胞坏死通常被视为一种促炎的细胞死亡机制。在人类急性胰腺炎中，观察到自噬体的积累和大量腺泡细胞坏死，急性胰腺炎是一种严重且潜在致命的炎症状态。我们研究了在慢性酒精摄入和急性内毒素血症诱导的大鼠急性胰腺炎模型中，影响腺泡细胞的细胞凋亡、自噬和坏死的发生率。我们观察到，酒精暴露和内毒素血症的组合导致自噬体的大量积累，而自溶体没有增加，同时伴有溶酶体蛋白 LAMP-2 的耗竭，LAMP-2 是自噬体与溶酶体适当融合所必需的。酒精加内毒素血症有利于从细胞凋亡向细胞坏死的转变，这可以通过组织病理学检查、ATP 水平降低、半胱天冬酶激活抑制以及促炎因子 HMGB1 的核释放来证明。重要的是，酒精性胰腺炎患者也表现出局部 LAMP-2 的耗竭，这再现了在动物模型中获得的结果。我们认为，胰腺炎中的腺泡细胞空泡化是由内毒素血症引起的 LAMP-2 耗竭介导的，这反过来又由于自溶体形成不足而促进了自噬体的积累。因此，我们假设溶酶体蛋白的耗竭可能在急性胰腺炎的发病机制中起关键作用。
