| Project/Area Number |
18590518
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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 |
Applied pharmacology
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
KATO Shinichi Kyoto Pharmaceutical University, Pharmaceutical Sciences, Lecturer (90281500)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,930,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | adjvant arthritic rat / non-steroidal anti-inflammatory drug / gastrointestinal iniury / nitric oxide(NO) / inducible NO svnthase(iNOS) / endothelial NO svnthase(eNOS) / toll-like receptor 4(TLR4) / macrophage / 非ステロイド性抗炎症薬(NSAID) / 内皮型NO合成酵素(eNOS) / リウマチ性関節炎 / 一酸化窒素合成酵素(NOS) / 非ステロイド系抗炎症薬 / 胃粘膜傷害 / 小腸粘膜障害 / シクロオキシゲナーゼ(COX) |
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| Research Abstract |
It is well known that non-steroidal antiinflammatry drug (NSAID) induces gastrointestinal (GI) injury as a side effect. In addition, the patients with rheumatoid arthritis have a greater risk in GI toxicity to NSAID than other NSAID users. In the present study, we mimicked this phenomenon in experimental animals and investigated this mechanism. The gastric and small intestinal injuries provoked by indomethacin and diclofenac were markedly aggravated in adjuvant-induced arthritic rats. The expression of iNOS and the number of macrophages expressed with TLR4, a receptor of bacterial lipopolysaccharide, were apparently augmented in the intestinal mucosa of arthritic rats. These finding suggest that the aggravation of NSAID-induced intestinal ulceration in arthritic rats is attributable to upregulation of iNOS/NO through enhancement of TLR4-positive macrophage invaded into the intestinal mucosa. We further observed the activation of NF-kappa B in the intestinal mucosa after the administration of indomethacin. Tacrolimus prevented the intestinal ulceration induced by NSAID through inhibition of NF-kappa B activation. On the other hand, we found the upregulation of endothelial NOS (eNOS) in addition to iNOS in the gastric mucosa of arthritic rats. We recently demonstrated that the formation of unstable monomeric eNOS, producing superoxide anion, is important in the pathogenesis of caerulein-induced acute pancreatitis in rats. However, we observed the overproduction of NO but not the formation of monomeric eNOS in the gastric mucosa of arthritic rats. The aggravation of NSAID-induced gastric damage was prevented partly by selective iNOS inhibitor and totally by non-selective NOS inhibitor. These finding suggest that the increased susceptibility of gastric mucosa to NSAID-induced damage in arthritic rats is attributable to the upregulation of eNOS/NO in addition to iNOS/NO.
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