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

众所周知，非甾体抗炎药（NSAID）会引起胃肠道（GI）损伤。此外，类风湿性关节炎患者对NSAID的胃肠道毒性风险高于其他NSAID使用者。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。消炎痛和双氯芬酸引起的大鼠胃和小肠损伤明显加重。关节炎大鼠肠黏膜中iNOS表达明显增强，表达细菌脂多糖受体TLR 4的巨噬细胞数量明显增多。这些发现表明，NSAID诱导的关节炎大鼠肠溃疡的加重是由于通过增强TLR 4阳性巨噬细胞侵入肠粘膜而上调iNOS/NO。我们进一步观察了吲哚美辛给药后肠粘膜NF-κ B B的活化。他克莫司可通过抑制NF-κ B的活化来预防NSAID诱导的肠溃疡。另一方面，我们发现在关节炎大鼠的胃粘膜中，除了诱导型一氧化氮合酶（iNOS）外，内皮型一氧化氮合酶（eNOS）也上调。我们最近发现，形成不稳定的单体eNOS，产生超氧阴离子，是重要的caerulein诱导大鼠急性胰腺炎的发病机制。然而，我们观察到过量生产的NO，但没有形成单体eNOS在关节炎大鼠的胃粘膜。选择性iNOS抑制剂可部分阻止NSAID所致胃损伤的加重，非选择性NOS抑制剂可完全阻止其加重。这些结果表明，增加胃粘膜对NSAID诱导的损伤的敏感性在关节炎大鼠是由于除了iNOS/NO上调eNOS/NO。

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.