Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage
Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage
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DOI：
10.1053/gast.2002.36558
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发表时间：
2002-11-01
期刊：
影响因子：
29.4
通讯作者：
Wallace, JL
中科院分区：
文献类型：
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作者：
Fiorucci, S;de Lima, OM;Wallace, JL
背景和目的：环加氧酶-2 (COX-2) 被认为有助于粘膜防御。阿司匹林乙酰化 COX-2 可产生抗炎物质 15(R)-epi-LXA(4)。我们确定阿司匹林通过 COX-2 触发的脂氧素 (LX) 产生是否会减少阿司匹林引起的大鼠胃损伤。方法：用阿司匹林加或减塞来考昔或罗非考昔治疗大鼠。测量LXA(4)的胃产生。研究了外源性LXA(4)或LXA(4)受体拮抗剂对胃对阿司匹林诱导损伤的抵抗力的影响。通过活体显微镜检查阿司匹林诱导的肠系膜小静脉中的白细胞粘附以及LXA(4)的作用。结果：塞来昔布和罗非昔布显着增加阿司匹林引起的胃损伤的严重程度。阿司匹林迅速上调胃中COX-2的表达，并引起胃15(R)-epi-LXA(4)产量显着增加，但塞来昔布可消除这种增加。 LXA(4)剂量依赖性（0.25-2.5杯/千克，腹腔注射）降低阿司匹林诱导的胃损伤的严重程度并抑制阿司匹林诱导的白细胞粘附，而LXA4拮抗剂具有相反的作用。结论：服用阿司匹林会导致 COX-2 产生 15(R)-epi-LXA(4) 增加。 LXA(4) 对胃粘膜具有非常有效的保护作用。阿司匹林和选择性 COX-2 抑制剂的共同给药会导致比单独使用任一药物产生的胃损伤严重得多。
Background & Aims: Cyclooxygenase-2 (COX-2) has been implicated as contributing to mucosal defense. Acetylation of COX-2 by aspirin can result in production of an antiinflammatory substance, 15(R)-epi-LXA(4). We determined whether aspirin-triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in the rat stomach. Methods: Rats were treated with aspirin plus or minus celecoxib or rofecoxib. Gastric generation of LXA(4) was measured. Effect of exogenous LXA(4) or an LXA(4) receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA(4), were examined by intravital microscopy. Results: Celecoxib and rofecoxib significantly increased the severity of aspirin-induced gastric damage. Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a significant increase in gastric 15(R)-epi-LXA(4) production, which was abolished by celecoxib. LXA(4) dose dependently (0.25-2.5 mug/kg, intraperitoneally) reduced the severity of aspirin-induced gastric damage and suppressed aspirin-induced leukocyte adherence, whereas an LXA4 antagonist had the opposite effects. Conclusions: Aspirin administration results in elevated production of 15(R)-epi-LXA(4) via COX-2. LXA(4) exerts very potent protective actions on the gastric mucosa. Co-administration of aspirin and a selective COX-2 inhibitor results in substantially more severe gastric injury than is produced with either agent alone.