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）会诱导胃肠道（GI）损伤作为副作用。此外，与其他NSAID使用者相比，类风湿关节炎患者对NSAID的毒素毒性风险更大。在本研究中，我们模仿了实验动物中的这种现象，并研究了这种机制。在佐剂引起的关节炎大鼠中显着加剧了由吲哚美辛和双氯芬酸造成的胃和小肠道损伤。在关节炎大鼠的肠粘膜中显然增加了用TLR4（TLR4）表达的巨噬细胞数量的表达。这些发现表明，NSAID诱导的关节炎大鼠肠溃疡的加剧归因于iNOS/NO的上调，通过增强TLR4阳性巨噬细胞的增强入侵肠粘膜。我们进一步观察到吲哚美辛给药后NF-kappa B的激活。他克莫司通过抑制NF-kappa B激活来防止NSAID诱导的肠溃疡。另一方面，除了关节炎大鼠的胃粘膜中，我们发现内皮NOS（ENOS）的上调。我们最近证明，产生超氧化阴离子的不稳定单体eNOS的形成在大鼠钙蛋白诱导的急性胰腺炎的发病机理中很重要。但是，我们观察到NO的过量生产，但不是在关节炎大鼠的胃粘膜中形成单体eNOS。选择性iNOS抑制剂和非选择性的NOS抑制剂完全阻止了NSAID诱导的胃损伤的加剧。这些发现表明，胃粘膜对关节炎大鼠NSAID诱导的损伤的敏感性增加归因于除iNOS/no之外的ENOS/NO的上调。