Preconditioning with death ligands FasL and TNF-alpha protects the cirrhotic mouse liver against ischaemic injury.
BACKGROUND
Ischaemic preconditioning is the preemptive 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 alpha 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.


CONCLUSIONS
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.
Jang
J-H
JH
Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery, University Hospital Zurich, Switzerland.
Moritz
W
W
Graf
R
R
Clavien
P-A
PA
D000818:Animals; D017209:Apoptosis; D004198:Disease Susceptibility; D053222:Fas Ligand Protein / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000502:physiology; D007511:Ischemia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D053222:Fas Ligand Protein; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1; D000637:Transaminases