Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion

Background and aim. Protease inhibitors attenuate ischemia/reperfusion inju ry. However, the underlying mechanisms by which protease inhibitors prevent reperfusion injury remain obscure. Neutrophils play an important role in r eperfusion injury. We studied the effects of urinary trypsin inhibitor (UTI ) on production of the C-X-C chemokine, cytokine-induced neutrophil chemoat tractant (CINC), by Kupffer cells during ischemia/reperfusion of the liver. Methods. Liver ischemia was induced in rats by occlusion of the portal vein for 30 min. UTI (50,000 U/kg) was injected intravenously 5 min before vasc ular clamping. Serum CINC concentrations were measured by enzyme-linked imm unosorbent assay. Levels of CINC mRNA in the liver were determined by North ern blot analysis, We also examined the inhibitory effects of UTI on in vit ro CINC production by peritoneal macrophages in response to neutrophil elas tase (NE), Results. Serum CINC concentrations increased and peaked 6 h after reperfusi on, However, pretreatment of animals with UTI blunted this increase in CINC and significantly reduced CINC mRNA levels in the liver after ischemia/rep erfusion. UTI also decreased neutrophil accumulation in the liver 24 h afte r reperfusion, In vitro CINC production by Kupffer cells from rats pretreat ed with UTI 3 h after ischemia/reperfusion was significantly decreased comp ared to those from untreated animals. UTI reduced NE activity in vitro in a dose-dependent manner, and UTI significantly reduced in vitro CINC product ion by peritoneal macrophages stimulated with NE, Conclusion. UTI reduces the production of CINC by Kupffer cells stimulated with NE, attenuating ischemia/reperfusion injury of the liver. (C) 2000 Aca demic Press.