Nagai Noriaki, Fukuhata Takashi, Ito Yoshimasa, Usui Shigeyuki, Hirano Kazuyuki
School of Pharmaceutical Sciences, Higashi-Osaka, Osaka 577-8502, Japan.
Toxicology. 2009 Jan 31;255(3):124-30. doi: 10.1016/j.tox.2008.10.005. Epub 2008 Oct 17.
It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAIDs-induced gastric lesions in comparison with other patients. The pathogenic mechanism of these lesions is not fully understood. We demonstrate whether interleukin 18 (IL-18) expression relate the aggravation of gastric lesion in adjuvant-induced arthritis (AA) rats following the oral administration of indomethacin. Arthritis was induced by injecting 50 microl of a suspension of 10mg/ml heat-killed butyricum (Mycobacterium butyricum) in Bayol F oil into the plantar region of the right hind foot and tail of Dark Agouti rats resulting in an arthritis incidence of 100%. Two weeks after injection, the rats were administered indomethacin (40mg/kg) orally, and were killed under deep ether anesthesia 6h later. The gastric mucosa was then examined. Oral administration of indomethacin caused hemorrhagic lesions in the gastric mucosa of AA rats, and the lesion score for AA rats following indomethacin treatment was significantly higher than for normal rats administered indomethacin. The expression of the IL-18 mRNA and mature IL-18 protein in the gastric mucosa of AA rats administered indomethacin were also higher in comparison with normal rats receiving indomethacin. In addition, interferon-gamma and nitric oxide levels in the gastric mucosa of AA rats were increased by the oral administration of indomethacin. It is possible that IL-18 expression in AA rats is more sensitive to indomethacin, and the IL-18 may play a role in the aggravation of gastric lesions in AA rats treated with indomethacin.
众所周知，非甾体抗炎药（NSAIDs）有显著的副作用，如胃肠病，与其他患者相比，服用NSAIDs的类风湿性关节炎患者更容易出现NSAIDs诱发的胃部病变。这些病变的致病机制尚未完全明确。我们研究了在佐剂诱导的关节炎（AA）大鼠口服吲哚美辛后，白细胞介素18（IL-18）的表达是否与胃部病变的加重有关。通过将50微升10mg/ml热灭活丁酸杆菌（丁酸分枝杆菌）悬浮液注入深色刺豚鼠右后足跖部和尾部的Bayol F油中诱导关节炎，关节炎发病率为100%。注射两周后，大鼠口服吲哚美辛（40mg/kg），6小时后在深度乙醚麻醉下处死。然后检查胃黏膜。口服吲哚美辛导致AA大鼠胃黏膜出现出血性病变，吲哚美辛治疗后AA大鼠的病变评分显著高于口服吲哚美辛的正常大鼠。与接受吲哚美辛的正常大鼠相比，给予吲哚美辛的AA大鼠胃黏膜中IL-18 mRNA和成熟IL-18蛋白的表达也更高。此外，口服吲哚美辛可使AA大鼠胃黏膜中的干扰素-γ和一氧化氮水平升高。AA大鼠中IL-18的表达可能对吲哚美辛更敏感，并且IL-18可能在接受吲哚美辛治疗的AA大鼠胃部病变加重中起作用。
