Jun Araya

TCV-116, an angiotensin II type 1 receptor antagonist, reduces hepatic ischemia-reperfusion injury in rats.

Background. In Pringle’s maneuver during liver surgery and liver transplantation, ischemia–reperfusion (I/R) is an unavoidable process, and protection against hepatic I/R injury is a major unresolved problem. Therefore, various pharmacologic approaches to prevent hepatic I/R injury are currently under trial. In this study, we investigated whether TCV-116, an angiotensin II type 1 receptor antagonist, can reduce this injury. Methods. The rats were pretreated either with TCV-116 (group 1) or with the vehicle alone (group 2). The rats in group 3 were not pretreated. Thereafter, they were subjected to partial hepatic I/R. Results. After reperfusion, the mean peak plasma concentrations of aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, and creatine kinase were lower in group 1 than in groups 2 and 3. The magnitude of hepatic injury was reduced in group 1 compared with that in groups 2 and 3. The mean peak plasma concentrations of tumor necrosis factor-&agr;, cytokine-induced neutrophil chemoattractants-1, and interleukin-6 were lower in group 1 than in groups 2 and 3. The number of neutrophils infiltrating the liver was also lower in group 1 than in groups 2 and 3. The mean peak plasma concentration of hepatocyte growth factor (HGF) was higher in group 1 than in groups 2 and 3. Conclusions. TCV-116 reduced the hepatic I/R injury by inhibiting inflammatory cytokine production and by enhancing HGF production.

Heat-shock protein-73 protects against small intestinal warm ischemiareperfusion injury in the rat

Abstract Background: The protective effects of heat-shock protein (hsp) in rat small intestinal warm ischemia-reperfusion (I/R) injury are poorly understood. Methods: Hsp-73 expression was induced in rat small intestine with use of sodium arsenite injected (6 mg/kg) through a catheter cannulated into the left common carotid artery 24 hours before ischemia (group 1). In the control group an equal volume of phosphate-buffered saline solution was injected (group 2). To block the induction of hsp-73 expression, sodium arsenate and quercetin (5 mg/kg) were injected (group 3). Results: The mean peak plasma levels of tumor necrosis factor-α and cytokine-induced neutrophil chemoattractant after reperfusion were lower in group 1 than in group 2. The tissue myeloperoxidase activity after reperfusion was lower in group 1 than in group 2. The mean peak plasma level of interleukin-10 after reperfusion was higher in group 1 than in group 2. The induction of hsp-73 expression reduced the synthesis of nitric oxide and the magnitude of the small intestinal warm I/R injury. The results in group 3 were similar to those in group 2. Conclusion: Hsp-73 protects against small intestinal warm I/R injury by inhibiting the synthesis of inflammatory cytokines and the activation of neutrophils and by accelerating the synthesis of anti-inflammatory cytokines. (Surgery 1999;125:385-95.)

Induction of heat shock protein-70 (hsp-70) by intraarterial administration of geranylgeranylacetone

IN TRANSPLANTATION, the principal problems are ischemia-reperfusion injury, preservation injury, rejection, infection, and graft-versus-host disease (GVHD), etc. Of these, ischemia-reperfusion/preservation injury is especially important, because it can cause primary nonfunction and its improvement is thereby crucial for the success of organ transplantation. Recently, there have been reports that showing that induction of heat shock protein (hsp) protects against ischemia-reperfusion injury and preservation injury. However, the mechanisms of this protective effect remain unknown and, as yet, a nontoxic clinical procedure for induction of hsp remains unavailable. In this study, we focused on geranylgeranylacetone (GGA), which is an antiulcer drug developed in Japan and used clinically for the treatment of gastric ulcer and gastritis. Its protective effects in other organs as well as the stomach have been reported; for instance, in one study, an improved histologic status in subjects with chronic hepatic injury was seen. It has been suggested that GGA may exert cytoprotective action through an increase of prostaglandin E2, 7 maintenance of cNOS activity, or induction of hsp. Therefore, in this study we investigate whether intraarterial administration of GGA to rats could induce expression of hsp-70 in various organs.