| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
[Background/Aims] Epidermal growth factor (EGF), which is one of trophic factors for intestinal adaptation after small bowel transplantation (SBT), has been shown to prevent bacterial translocation (BT) in a variety of experimental animal models. Nitric oxide (NO) may be an important protective molecule against gut-derived sepsis, bum injury, intestinal ulcerogenecity, intestinal lesions, and SBT. Recently we found that EGF increased the production of NO in rat intestinal epithelial cells stimulated by pro-inflammatory cytokine, interleukin (IL)-1β, suggesting that NO may be involved in the cytoprotective effects of EGF against intestinal injury. We examined whether drugs, which have protective effects in various organ injuries, influence the inducible nitric oxide synthase (iNOS) expression and NO production in intestinal epithelium.
[Methods] Cultured rat intestinal epithelial cells (IEC-6) were treated with IL-1β /EGF in the presence of drugs, and the induction of iNOS and NO product
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ion was analyzed.
[Results] IEC-6 stimulated the production of NO in the presence of IL-1β /EGF. The addition of anti-oxidant such as a-lipoic acid and cysteamine, free radical scavenger edaravone (Mitsubishi Wellpharma, Japan), and HMG-CoA reductase inhibitor/statin pitavastatin (Kowa, Japan) further increased the NO production. Among them, pitavastatin (10-100 μM) accelerated the NO production in the presence of IL-1β as in the case of EGF, showing a maximal effect at the concentration of 50 μM. Pitavastatin alone had no effect on the production of NO. Pitavastatin increased the levels of iNOS mRNA, followed by the increase of iNOS protein, which in turn enhanced the NO production. Exogenous addition of mevalonate, which is a key intermediate of cholesterol biosynthesis and is reduced by statins, blocked the increased production of NO, and increased expression of iNOS mRNA and protein. This suggests that the stimulatory effect of pitavastatin is at least in part through the inhibition of cholesterol biosynthesis.
[Conclusion] Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors), which are originally used to lower plasma cholesterol levels, are increasingly recognized as anti-inflammatory agents. Our results indicate that pitavastatin up-regulate the induction of iNOS expression and increase the production of NO, resulting in the protective effect in intestinal epithelial cells during inflammation. Pitavastatin as well as EGF may accelerate the graft adaptation through the regulation of NO production in SBT. Less
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