Background and hypothesis: 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.
Methods: 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.
Results: 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 κB (NFκB) and tumour necrosis factor α (TNFα) 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 NFκB as well as reduced induction of TNFα mRNA synthesis and neutrophil infiltration. By contrast, infection with L monocytogenes showed comparable activation of NFκB and hepatic recruitment of neutrophils 12 h after infection.
Conclusion: 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.
- CBDL, common bile duct ligation
- EMSA, electrophoretic mobility shift assay
- LPS, lipopolysaccharide
- NFκB, nuclear factor κB
- SBDL, selective bile duct ligation
- TNFα, tumour necrosis factor α
Statistics from Altmetric.com
Published Online First 8 June 2006
Funding: This study was supported by grants from the Swiss National Foundation (32-61411 to P-AC and PPOOB-108511/1 to GAK-U), the Hartmann Müller Foundation (to PG) and the Gebert Ruf Foundation (to WJ). PG, AAN and KSL are participants of the postgraduate course for experimental medicine and biology at the University of Zurich, Zürich, Switzerland, with scholarships from the University of Zurich (to PG), the Swiss National Foundation (to AAN) and the Deutsche Forschungsgemeinschaft (to KSL).
Competing interests: None.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.