Preconditioning with death ligands FasL and TNF-α protects the cirrhotic mouse liver against ischaemic injury

Jang, J.-H.; Moritz, W.; Graf, A.; Clavien, P.-A.
April 2008
Gut;Apr2008, Vol. 57 Issue 4, p492
Academic Journal
Background: lschaemic preconditioning is the pre-emptive proven strategy to reduce ischaemic injury in the liver, but it can be harmful in the elderly or in patients with liver diseases. lschaemic preconditioning induces a protective effect via activation of oxidative stress. We hypothesised that Fas ligand and tumour necrosis factor α can induce a similar response. Therefore, we tested if death ligands could mimic ischaemic preconditioning. Methods: lschaemia was maintained for 60 mm in cirrhotic mice. Death ligands were given 40 mm before ischaemia. lschaemic injury was assessed by histology and biochemical assays. To elucidate the mechanism, we used zinc protophorphyrin, an inhibitor of haem oxygenase-1 (HO-1), and gadolinium chloride, an inhibitor of Kupffer cells. Results: Compared with the control group, death ligand preconditioning strongly reduced all markers of injury: serum transaminase levels, necrosis and apoptosis. Preconditioning caused an upregulation of HO-1, predominantly in macrophages. When zinc protophorphyrin or gadolinium chloride was applied prior to preconditioning, the beneficial effect of preconditioning was lost. Conclusion: These results demonstrate that ischaemic preconditioning can be replaced by death ligand preconditioning in the cirrhotic liver to prevent ischaemic injury. The protective mechanism depends on HO-1 induction in macrophages. These results open doors for novel hepato-protective strategies in liver surgery and transplantation.


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