Preconditioning with death ligands FasL & TNF-á protects the cirrhotic mouse liver against ischemic injury

Abstract

Background:<br> Ischemic preconditioning is the pre-emptive proven strategy to reduce ischemic injury in the liver, but it can be harmful in the elderly or patients with liver diseases. Ischemic preconditioning induces protective effect via activation of oxidative stress. We hypothesized that Fas ligand and tumor necrosis factor can induce a similar response. Therefore, we tested if death ligands could mimic ischemic preconditioning. Ischemia was performed for 60 minutes in cirrhotic mice.

Methods:<br> Death ligands were given 40 minutes before ischemia. Ischemic injury was assessed by histology, and biochemical assays. To elucidate the mechanism, we used zinc- protophorphyrin, an inhibitor of heme oxygenase-1 and gadolinium chloride, an inhibitor of Kupffer cells.

Results:<br> Compared to the control group, death ligand preconditioning strongly reduced all markers of injury: serum transaminase levels, necrosis and apoptosis. Preconditioning caused an up-regulation of heme oxygenase-1, predominantly in macrophages. When zinc-protophorphyrin or gadolinium chloride was applied prior to preconditioning, the beneficial effect of preconditioning was lost.

Conclusion:<br> These results demonstrate that ischemic preconditioning can be replaced by death ligand preconditioning in the cirrhotic liver to prevent ischemic injury. The protective mechanism is depending on heme oxygenase-1 induction in macrophages. These results open doors for novel hepato-protective strategies in liver surgery and transplantation.