Kiyoshi Kawata

Effect of FR167653 on Small Bowel Ischemia-Reperfusion Injury in Dogs

IL-1 and TNF-α are known to be pleiotropiccytokines associated with various inflammatoryconditions such as small intestinal injury afterischemia-reperfusion. FR167653 has been characterized asa potent suppressant of IL-1 and TNF-αproduction. The effect of FR167653 on intestinalreperfusion injury was investigated in a warm ischemiamodel of the canine gut. Sixteen mongrel dogs weredivided into two groups: a control group and a FR groupto which FR167653 was administered. Both the superiormesenteric artery and vein were clamped for 2 hr.Arterial pH, hepatic venous hemoglobin oxygensaturation, intramucosal pH, and the survival rate werewell maintained in the FR group in comparison with thecontrol group after reperfusion. FR167653 inhibited theexpression of IL-1β mRNA. Histologically,ischemia-reperfusion injury was more severe in the control groupthan the FR group. This study suggests that FR167653inhibits proinflammatory cytokines and amelioratesischemia-reperfusion injury of the smallintestine.

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. STUDY DESIGN 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.

A Spontaneous Nitric Oxide Donor Ameliorates Small Bowel Ischemia–Reperfusion Injury in Dogs

Nitric oxide (NO) appears to play an important role in tissue injury during reperfusion. FK409 is the first spontaneous NO donor that increases plasma guanosine 3`,5`-cyclic monophosphate. We investigated the effects of the NO donor FK409 (FK) on ischemia–reperfusion injury in a canine warm ischemia model. Fourteen adult mongrel dogs were divided into two groups: the control group and the FK group, which received FK. The superior mesenteric artery and vein were both clamped for 2 h and then reperfused for 12 h. Arterial and intramucosal pH were well maintained in the FK group in comparison with the control group. Histologically, ischemia–reperfusion injury was significantly more severe in the control group than in the FK group. The serum NO levels were significantly higher in the FK group than in the control group during FK administration. FK409 has protective effects on ischemia–reperfusion injury of the small intestine due to NO release.

Effect of lazaroid U-74389G on prolonged hepatic ischemia-reperfusion injury.

IN SPITE of progress in the field on liver transplantation, graft dysfunction due to ischemia-reperfusion injury frequently occurs after revascularization. Research efforts are crucial to determine the mechanism of reperfusion injury and to reduce its incidence. Lazaroids are a group of new synthetic 21-aminosteroids that inhibit iron-dependent lipid peroxidation without glucocorticoid and mineral ocorticoid actions. Lazaroids suppress cytokine production, adhesion molecule expression, and neutrophile activation and infiltration. We examined the effect of Lazaroid U-74389G on ischemia-reperfusion injury of the canine liver.