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


Jang, J H; Moritz, W; Graf, R; Clavien, P A (2008). Preconditioning with death ligands FasL and TNF-alpha protects the cirrhotic mouse liver against ischaemic injury. Gut, 57(4):492-499.

Abstract

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. 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.

Abstract

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. 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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2008
Deposited On:16 Dec 2008 12:02
Last Modified:05 Apr 2016 12:42
Publisher:BMJ Publishing Group
ISSN:0017-5749
Publisher DOI:https://doi.org/10.1136/gut.2007.137703
PubMed ID:18079283

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