Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver.
OBJECTIVE
While ischemic preconditioning confers significant protection against subsequent prolonged periods of ischemia, the mechanisms triggering protection remain speculative. We hypothesize that a sub-lethal oxidative stress during ischemic preconditioning induces defense mechanisms preventing subsequent lethal injury.


METHODS
We used mouse models of partial and total hepatic ischemia for 75 min. Ischemic preconditioning consisted of 10-min ischemia and 15-min reperfusion prior to the prolonged ischemic insult.


RESULTS
Tissue levels of peroxides increased about three times after 10 min of ischemia and normalized within 15 min of reperfusion. This limited oxidative stress during ischemic preconditioning prevented the negative effects of subsequent prolonged ischemia as assessed by AST-levels, TUNEL-staining of hepatocytes and animal survival. N-Acetylcysteine inhibited the mild oxidative burst of ischemic preconditioning, and fully reversed the protective effects of preconditioning. The protective role of a sub-lethal oxidative stress was supported by the benefit of delivery of an H2O2-analog through the portal vein prior to a long ischemic insult. This challenge conferred similar protection as ischemic preconditioning.


CONCLUSIONS
We conclude that the mild burst of oxidative stress generated during ischemic preconditioning triggers protective mechanisms against subsequent, otherwise lethal, ischemic injury. The pathway possibly includes enhancement of natural anti-oxidative stress mechanisms.
Rüdiger
Hannes A
HA
Laboratory for Hepatobiliary Surgery and Liver Transplantation, Department of Visceral Surgery and Transplantation, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
Graf
Rolf
R
Clavien
Pierre-Alain
PA
D000818:Animals; D017209:Apoptosis; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D010545:Peroxides / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
D010545:Peroxides