ONO-5046. A specific neltroph1l elastase inhibitor, improves hepatic tissue blood flow after tschemia/reperfusion of the rat liver

Masakazu Mon, Kenji Okajima, Naoaki Harada, Shigeki Kushimoto, Hiraaka Isobe, Kazunori Munkami, Hiroaki Okabe, Takayuki Noguchi

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Neutrophils piay an important role in ischemiaAtperfuswo (lyR)induced liver injury by releasing various mediators such as neutrophil elastate (NE) that is capable of damaging endothelial cells. Since NE inhibits prostacyclin (PGI:) production by endothelial cells in vitro, it is possible that NE may contribute 10 decrease in hepatic tissue blood flow observed in Mi-induced liver injury. We examined whether NE is impticaied in I/R-induced reduction of hepatic tissue blood flow via impairment of the endothelial production of PGI2 in rats. Methods: Male Wistar rats (220-280 g) were drvided into four groups: ONO5046 (50 mg/kg/h iv)-treated I/R, iloprost (a stable PGI2 analog, 100 ngg/min ivHreated I/R, vehicle (normal jatineHreated I/R, and sham-operation. The drags were continuously infused for 4 h from the beginning of the ischémie period. The ischemia of the median and left lobe of me liver was produced by damping the left branches of the portal vein and hepatic artery for 60 min. In each group, tepsnse subgroups of animals (n=5) were used to determine the following: hepatic tissue blood flow (by a laser-Doppler flowmeter), hepatic level of 6-keto-prostagiandin Fia (6-keto-PGFia, a stable metabolite of PGI2), bile flow, and senro levels of transaminases. Data were analyzed using unpaired Student's t test or ANOVA followed by multiple comparison test (Scherte). Results: ONO-5046 significantly prevented IR-induced decrease in the hepatic tissue Mood flow. The hepatic level of 6-keto-PGFio transiently increased l h after hepatic I/R. ONO-5046 significantly inhibited the decrease in hepatic level of 6keto-PGFia at 2 and 3 h after reperfusion. A reduction of bile flow rate and incicsae in serum levels of transaminases after hepatic I/R were significandy inhibited by administration of ONO- 5046. Continuous intravenous infusion of iloprost exhibited effects similar to those of ONO-5046. Conclusions: ME can be implicated in lyR-induced liver injury by reducing the hepatic tissue Mood flow via impairment of the endothelial production of PGI2.

Original languageEnglish
Pages (from-to)A140
JournalCritical care medicine
Volume26
Issue number1 SUPPL.
Publication statusPublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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