Kotaro Iwanami

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.

Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs.

BACKGROUND Nitric oxide attenuates ischemia-reperfusion injury by maintaining organ circulation through its actions as a vasoregulator, an inhibitor of platelet aggregation, and an attenuator of leukocyte adhesion. Otherwise, the harmful effects of enhanced nitric oxide production induced by inducible nitric oxide synthase mediate ischemia-reperfusion injury. FK409 has been characterized as a spontaneous nitric oxide donor. The aim of this study was to evaluate the effects of FK409 on extended liver resection with ischemia using a canine model. STUDY DESIGN Adult mongrel dogs were subjected to 60 minutes of warm ischemia by partial inflow occlusion. After reperfusion the nonischemic lobes were resected and the remnant liver function was evaluated. The dogs were divided into two groups: the control group (n = 7) and the FK409 group (n = 6), which was given FK409 through the portal vein. RESULTS The hepatic tissue blood flow, serum liver enzymes levels, and serum endothelin-1 level after reperfusion were significantly better in the FK409 group than in the control group. Electron microscopy demonstrated that endothelial cells and Ito cells were well-preserved in the FK409 group. The 3-day survival rate was statistically better in the FK409 group (67%) than in the control group (14%). CONCLUSIONS FK409 appears to have protective effects during extended liver resection with ischemia.

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 Pulmonary Ischemia - Reperfusion Injury in Dogs

Lipid peroxidation induced by oxygen free radicals is a contributing factor in ischemia-reperfusion injury. Lazaroid U-74389G (LAZ-G) is a group of new synthetic 21-aminosteroids and inhibits irondependent lipid peroxidation. We investigated the effects of LAZ-G on pulmonary ischemia-reperfusion injury in dogs. Twenty dogs were divided into three groups. In the LAZ-G group (

Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs

BACKGROUND FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model. STUDY DESIGN The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction. RESULTS Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group. CONCLUSIONS FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.

Effect of short-term coronary perfusion after cold storage for long-term heart preservation: a comparative study of University of Wisconsin solution and diluted blood as the perfusate.

THE DURATION of preservation is currently limited to 4 to 6 hours in clinical heart transplantation. Extending the period of preservation could expand the available donor pool. We previously attempted to combine simple cold storage and coronary perfusion and reported that additional coronary perfusion after cold storage was useful for myocardial protection and improved graft viability. In this study, we compared two different solutions as the perfusate, which was assessed through preservation and transplantation.

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.