Mechanism elucidation for the aggravation of gastrointestinal injury induced by non-steroidal anti-inflammatory drugs during chronic arthritis.

慢性关节炎期间非甾体类抗炎药加重胃肠道损伤的机制阐明。

基本信息

批准号：
18590518
负责人：
KATO Shinichi
金额：
$ 2.52万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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.

众所周知，非甾体类抗炎药（NSAID）会引起胃肠道（GI）损伤。此外，类风湿性关节炎患者比其他 NSAID 使用者有更大的 NSAID 胃肠道毒性风险。在本研究中，我们在实验动物中模拟了这种现象并研究了这种机制。在佐剂诱发的关节炎大鼠中，吲哚美辛和双氯芬酸引起的胃和小肠损伤明显加重。关节炎大鼠肠粘膜中 iNOS 的表达和细菌脂多糖受体 TLR4 表达的巨噬细胞数量明显增加。这些发现表明，关节炎大鼠中 NSAID 诱导的肠溃疡加重是由于 TLR4 阳性巨噬细胞侵入肠粘膜的增强，导致 iNOS/NO 上调。我们进一步观察了给予吲哚美辛后肠粘膜中NF-κB的激活情况。他克莫司通过抑制 NF-κ B 激活来预防 NSAID 诱导的肠道溃疡。另一方面，我们发现关节炎大鼠胃粘膜中除 iNOS 外，内皮型一氧化氮合酶 (eNOS) 也上调。我们最近证明，不稳定单体 eNOS 的形成，产生超氧阴离子，在雨蛙素诱导的大鼠急性胰腺炎的发病机制中很重要。然而，我们在关节炎大鼠的胃粘膜中观察到NO过量产生，但没有观察到单体eNOS的形成。选择性 iNOS 抑制剂可以部分阻止 NSAID 引起的胃损伤的加重，而非选择性 NOS 抑制剂可以完全阻止 NSAID 引起的胃损伤的加重。这些发现表明，关节炎大鼠胃粘膜对 NSAID 引起的损伤的敏感性增加可归因于除了 iNOS/NO 之外 eNOS/NO 的上调。