2000 Fiscal Year Final Research Report Summary
Regulation of pro- and anti-inflammatory cytokine responses by Kupffer cell in endotoxin-enhanced reperfusion injury after total hepatic ischemia
| Project/Area Number |
10671169
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
SUZUKI Shohachi Hamamatsu University School of Medicine, Department of Surgery II, Assistant Professor, 医学部・附属病院, 講師 (20196827)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Satoshi Hamamatsu University School of Medicine, Department of Surgery II, Professor, 医学部, 教授 (00090027)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Hepatic ischemia / Reperfusion injury / Kupffer cell / TNF-α / MIP-2 / Gadolinium chloride / Endotoxin / IL-10 |
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| Research Abstract |
Background. This study was designed to investigate the implication of Kupffer cell for pro- and anti-inflammatory cytokine responses in endotoxin-enhanced reperfusion injury after total hepatic ischemia.
Methods. Male rats pretreated with either normal saline solution (NS group) or gadolinium chloride (7 mg/kg) for 2 days to inhibit Kupffer cell function (GC group) were subjected to 60 minutes of total hepatic ischemia. These animals given either normal saline solution or sublethal endotoxin (1 mg/kg) via the portal vein at reperfusion were subdivided into NS-N, NS-E, GC-N and GC-E groups. In addition to 7-day survival rates, plasma aspartate aminotransferase (AST), tumor necrosis factor alpha (INF-α), macrophage inflammatory protein-2 (MIP-2), and interleukin-10 (IL-10) levels and hepatic neutrophil infiltration were determined 1, 3, and 6 hours after reperfusion.
Results. All animals without endotoxin administration at reperfusion tolerated 60 minutes of hepatic ischemia. While 7-day survival rate of NS-E group was reduced to 30%, that of GC-E group significantly improved to 80%. Cytokine responses in NS-E group were composed of the maximum TNF-α and IL-10 levels 1 hour after reperfusion with a subsequent peak of MIP-2 levels. The highest AST levels and extensive hepatic necrosis with more neutrophil infiltration were observed 6 hours after reperfusion. Pretreatment with GdCl3 significantly suppressed TNF-α production and increased IL-10 production 1 hours of reperfusion when compared to those in NS-E group, which led to decline in MIP-2 production and amelioration of functional and structural liver damage.
Conclusions. Kupffer cells were implicated in endotoxin-enhanced reperfusion injury after hepatic ischemia with increased MIP-2 production mediated by TNF-α and IL-10. Blockade of Kupffer cells may have a great potential to attenuate the insult via modulation of these cytokine responses.
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