The effect of cyclooxygenase-2 inhibitor FK3311 on ischemia-reperfusion injury in a canine total hepatic vascular exclusion model.
BACKGROUND
Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model.


METHODS
Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted.


RESULTS
Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower.


CONCLUSIONS
FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.
Sunose
Y
Y
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Takeyoshi
I
I
Ohwada
S
S
Tsutsumi
H
H
Iwazaki
S
S
Kawata
K
K
Kawashima
Y
Y
Tomizawa
N
N
Matsumoto
K
K
Morishita
Y
Y
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006820:Hyaluronic Acid / Q000097:blood; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007958:Leukocyte Count; D008099:Liver / Q000473:pathology; D008102:Liver Circulation; D009504:Neutrophils; D011451:Prostaglandin-Endoperoxide Synthases; D011897:Random Allocation; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D013929:Thromboxane B2 / Q000097:blood
D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C085566:FK 3311; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D006820:Hyaluronic Acid; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000410:Alanine Transaminase