Heme oxygenase-1 induction by the clinically used anesthetic isoflurane protects rat livers from ischemia/reperfusion injury.
OBJECTIVE
It was the aim of this study to characterize the influence of isoflurane-induced heme oxygenase-1 (HO-1) expression on hepatocellular integrity after ischemia and reperfusion.


BACKGROUND
Abundant experimental data characterize HO-1 as one of the most powerful inducible enzymes that contribute to the protection of the liver and other organs after harmful stimuli. Therapeutic strategies aimed at utilizing the protective effects of HO-1 are hampered by the fact that most pharmacological inducers of this enzyme perturb organ function by themselves and are not available for use in patients because of their toxicity and undesirable or unknown side effects.


METHODS
Rats were pretreated with isoflurane before induction of partial hepatic ischemia (1 hour) and reperfusion (1 hour). At the end of each experiment, blood and liver tissue were obtained for molecular biologic, histologic, and immunohistochemical analyses.


RESULTS
Isoflurane pretreatment increased hepatic HO-1 mRNA, HO-1 protein, HO enzyme activity, and decreased plasma levels of AST, ALT, and alpha-GST. Histologic analysis of livers obtained from isoflurane-pretreated rats showed a reduction of necrotic areas, particularly in the perivenular region, the predominant site of isoflurane-induced HO-1 expression. In addition, sinusoidal congestion that could otherwise be observed after ischemia/reperfusion was inhibited by the anesthetic. Furthermore, isoflurane augmented hepatic microvascular blood flow and lowered the malondialdehyde content within the liver compared with control animals. Administration of tin protoporphyrin IX inhibited HO activity and abolished the isoflurane-induced protective effects.


CONCLUSIONS
This study provides first evidence that pretreatment with the nontoxic and clinically approved anesthetic isoflurane induces hepatic HO-1 expression, and thereby protects rat livers from ischemia/reperfusion injury.
Schmidt
Rene
R
Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Hugstetterstrasse 55, D-79106 Freiburg, Germany. rene.schmidt@uniklinik-freiburg.de
Tritschler
Eva
E
Hoetzel
Alexander
A
Loop
Torsten
T
Humar
Matjaz
M
Halverscheid
Leonie
L
Geiger
Klaus K
KK
Pannen
Benedikt H J
BH
D000704:Analysis of Variance; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001783:Blood Flow Velocity; D015152:Blotting, Northern; D015153:Blotting, Western; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007530:Isoflurane / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply* / Q000201:enzymology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008833:Microcirculation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*
D000777:Anesthetics; D008315:Malondialdehyde; D007530:Isoflurane; D051547:Heme Oxygenase-1