Protective effects of ischemic preconditioning and application of lipoic acid prior to 90 min of hepatic ischemia in a rat model.
OBJECTIVE
To compare different preconditioning strategies to protect the liver from ischemia/reperfusion injury focusing on the expression of pro- and anti-apoptotic proteins. Interventions comprised different modes of ischemic preconditioning (IP) as well as pharmacologic pretreatment by alpha-lipoic acid (LA).


METHODS
Several groups of rats were compared: sham operated animals, non-pretreated animals (nt), animals receiving IP (10 min of ischemia by clamping of the portal triad and 10 min of reperfusion) prior to sustained ischemia, animals receiving selective ischemic preconditioning (IPsel, 10 min of ischemia by selective clamping of the ischemic lobe and 10 min of reperfusion) prior to sustained ischemia, and animals receiving 500 micromol alpha-LA injected i.v. 15 min prior to the induction of 90 min of selective ischemia.


RESULTS
Cellular damage was decreased only in the LA group. TUNEL-positive hepatocytes as well as necrotic hepatocyte injury were also decreased only by LA (19 +/- 2 vs 10 +/- 1, P < 0.05 and 29 +/- 5 vs 12 +/- 1, P < 0.05). Whereas caspase 3- activities in liver tissue were unchanged, caspase 9- activity in liver tissue was decreased only by LA pretreatment (3.1 +/- 0.3 vs 1.8 +/- 0.2, P < 0.05). Survival rate as the endpoint of liver function was increased after IP and LA pretreatment but not after IPsel. Levels of lipid peroxidation (LPO) in liver tissue were decreased in the IP as well as in the LA group compared to the nt group. Determination of pro- and anti-apoptotic proteins showed a shift towards anti-apoptotic proteins by LA. In contrast, both our IP strategies failed to influence apoptotic cell death.


CONCLUSIONS
IP, consisting of 10 min of ischemia and 10 min of reperfusion, protects only partly against ischemia/reperfusion injury of the liver prior to 90 min of selective ischemia. IPsel did not influence ischemic tolerance of the liver. LA improved tolerance to ischemia, possibly by downregulation of pro-apoptotic Bax.
University Hospital Mainz, Department of General and Abdominal Surgery, Langenbeckstrasse 1, 55131 Mainz, Germany. duenschede@ach.klinik.uni-mainz.de
Friedrich
F
Duenschede
Kirsten
K
Erbes
Nina
N
Riegler
Patrick
P
Ewald
Achim
A
Kircher
Stefanie
S
Westermann
Arno
A
Schad
Imke
I
Miesmer
Simon
S
Albrecht-Schöck
Ines
I
Gockel
Alexandra K
AK
Kiemer
Theodor
T
Junginger
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004195:Disease Models, Animal; D005982:Glutathione Transferase / Q000097:blood; D007511:Ischemia / Q000150:complications* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019194:Ischemic Preconditioning / Q000379:methods*; D007527:Isoenzymes / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008063:Thioctic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494828:Bax protein, rat; D007527:Isoenzymes; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D008063:Thioctic Acid; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9