Georgiev P, Navarini A A, Eloranta J J, Lang K S, Kullak-Ublick G A, Nocito A, Dahm F, Jochum W, Graf R, Clavien P-A
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Zürich, Switzerland.
Gut. 2007 Jan;56(1):121-8. doi: 10.1136/gut.2006.097170. Epub 2006 Jun 8.
Cholestasis is associated with high morbidity and mortality in patients undergoing major liver surgery, but the mechanisms responsible remain elusive. Increased ischaemic liver injury and inflammation may contribute to the poor outcome.
Common bile duct ligation (biliary obstruction with hyperbilirubinaemia) or selective ligation of the left hepatic duct (biliary obstruction without hyperbilirubinaemia) was performed in C57BL/6 mice before 1 h of hepatic ischaemia and 1, 4 or 24 h of reperfusion. Infection with the intracellular hepatic pathogen Listeria monocytogenes for 12 and 48 h was used to study ischaemia-independent hepatic inflammation.
Cholestatic mice showed considerable protection from ischaemic liver injury as determined by transaminase release, histological liver injury and neutrophil infiltration. In cholestatic mice, reduced injury correlated with a failure to activate nuclear factor kappaB (NFkappaB) and tumour necrosis factor alpha (TNFalpha) mRNA synthesis, two key mediators of post-ischaemic liver inflammation. After selective bile duct ligation, both the ligated and the non-ligated lobes showed blocked activation of NFkappaB as well as reduced induction of TNFalpha mRNA synthesis and neutrophil infiltration. By contrast, infection with L monocytogenes showed comparable activation of NFkappaB and hepatic recruitment of neutrophils 12 h after infection.
Cholestasis does not increase but rather dramatically protects the liver from ischaemic injury and inflammation. This effect is mediated by a systemic factor, but not bilirubin, and is associated with a preserved capacity to trigger an inflammatory response to other stimuli such as a bacterial pathogen.
胆汁淤积与接受大肝脏手术患者的高发病率和死亡率相关，但其潜在机制仍不清楚。缺血性肝损伤和炎症增加可能导致不良预后。
在C57BL/6小鼠肝脏缺血1小时及再灌注1、4或24小时前，进行胆总管结扎（伴有高胆红素血症的胆道梗阻）或左肝管选择性结扎（不伴有高胆红素血症的胆道梗阻）。利用细胞内肝脏病原体单核细胞增生李斯特菌感染12和48小时来研究非缺血性肝脏炎症。
通过转氨酶释放、肝脏组织学损伤及中性粒细胞浸润测定，胆汁淤积小鼠对缺血性肝损伤显示出显著的保护作用。在胆汁淤积小鼠中，损伤减轻与未能激活核因子κB（NFκB）及肿瘤坏死因子α（TNFα）mRNA合成相关，这两者是缺血后肝脏炎症的两个关键介质。选择性胆管结扎后，结扎及未结扎叶均显示NFκB激活受阻以及TNFα mRNA合成诱导及中性粒细胞浸润减少。相比之下，单核细胞增生李斯特菌感染在感染后12小时显示出类似的NFκB激活及中性粒细胞肝脏募集。
胆汁淤积不会增加反而能显著保护肝脏免受缺血性损伤和炎症。这种效应由一种全身因素介导，但不是胆红素，并且与对其他刺激（如细菌病原体）触发炎症反应的能力保留有关。
