Preconditioning with death ligands FasL and TNF-α protects the cirrhotic mouse liver against ischaemic injury
- Swiss HPB (Hepato–Pancreato–Biliary) Center, Department of Surgery, University Hospital Zurich, Switzerland
- P A Clavien, Department of Surgery, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland;
- Revised 13 November 2007
- Revised 20 November 2007
- Published Online First 13 December 2007
Background: Ischaemic 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. Ischaemic 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: Ischaemia was maintained for 60 min in cirrhotic mice. Death ligands were given 40 min before ischaemia. Ischaemic 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.
Funding: This study was supported by Korea Science & Engineering Foundation (KOSEF; M01-2004-000-20431-0), Seoul, Korea (to J-H Jang), Swiss National Foundation (SNF; 3200B0-109906), Bern, Switzerland (to P-A Clavien).
Competing interests: None.