2000 Fiscal Year Final Research Report Summary
The study of mechanism of liver cell injury induce by edotoxin shock and ischemia, and its clinical application
| Project/Area Number |
10671116
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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 |
General surgery
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MARUBAYASHI Seiji Hiroshima University, Medical Hospital, Associate Professor, 医学部・附属病院, 助教授 (80144814)
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| Co-Investigator(Kenkyū-buntansha) |
SUGINO Keizo Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (80162882)
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| Project Period (FY) |
1998 – 2000
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| Keywords | endotoxin shock / liver injury / Nuclear factor -kB / TNF-α / lazaroid / Kupffer cells / cell injury / cytokine |
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| Research Abstract |
Lazaroid (21-aminosteroid) is a nonglucocorticoid steroid that was synthesized to inhibit lipid peroxidation without the glucocorticoid activity. The present study was undertaken to determine whether lazaroid could suppress pro-inflammatory gene up-regulation through inhibition of nuclear factor-kB (NF-kB) activation in Kupffer cells.
Lazaroid treatment significantly increased survival rates 48 hours after LPS injection and protected against LPS-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, TNF-α, hepatic enzyme release, and neutrophil infiltration in the liver. Lararoid also showed inhibitory effects on NF-kB activation in the liver. In the experiment of Kupffer cells, lazaroid treatment suppressed the release of TNF-α in a dose dependent manner. Lazaroid also inhibited the increase of TNF mRNA expression and NF-kB activation in Kupffer cells 1 h and 30 min, respectively, after LPS addition. Furthermore, lazaroid treatment suppressed the degradation of IkB proteins in LPS-stimulated Kupffer cells.
These results suggest that lazaroid can suppress proinflammatory gene up-regulation through inhibition of NF-kB activation in Kupffer cells and that this is a promising new drug for the treatment of endotoxin shock.
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