| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Male Wistar rats were exposed to gut ischemia for 30 min followed by reperfusion. Intravital videomicroscopy was used to monitor leukocyte recruitment and the number of nonperfused sinusoids (NPS). Plasma ALT, tumor necrosis factor (TNF)-α and endotoxin levels as well as intestinal mucosal permeability (IMP) were also monitored. In separate experiments, ethanol was administered (by gastric tube) before gut ischemia. Same experiments wee peformed in male Wistar rats, pair-fed for 6 weeks with either a liquid diet containing EtOH or an isocaloric control diet. In control rats, gut I/R increased the number of stationary leukocytes and NPS.It also elevated the plasma ALT, TNF-α and endotoxin levels, with a corresponding increase in IMP.Low-dose ethanol consumption blunted gut I/R-induced leukostasis in the midzonal region and it reduced the I/R-induced elevations in plasma TNF-α and ALT.However, high-dose ethanol consumption aggravated the gut I/R-induced increases in leukostasis in the pe
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ricentral region and it exacerbated the increases in plasma endotoxin and ALT.Ethanol consumption, at either dose, did not affect the gut I/R-induced increase in the IMP.Pretreatment with an NO synthase inhibitor, NG-monomethyl-L-arginine, diminished the protective effects of low dose ethanol. In rats fed EtOH chronically, the gut I/R-induced increases in NPS and leukostasis were blunted in the midzonal region, while exaggerated letukostasis was noted in the pericentral region and terminal hepatic venules (THV). Chronic EtOH consumption also enhanced the gut I/R-induced increase in plasma ALT levels. The exaggerated responses to gut I/R normally seen in EtOH-fed rats, were largely prevented by pretreatment with a blocking anti ICAM-1 monoclonal antibody. These results suggest that low-dose ethanol consumption attenuates the hepatic imflammatory responses, microvascular dysfunction and hepatocellular injury elicited by gut I/R via an increase in sinusoidal NO levels, while high-dose ethanol consumption appears to significantly aggravate these gut I/R-induced responses. These results also suggest that chronic EtOH consumption enhances the gut I/R-induced hepatic microvascular dysfunction in the pericentral region and THV by an enhanced expression of ICAM-1, which may contribute to the corresponding enhancement of liver (hepatocellular) injury. Less
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