Tanaka A, Araki H, Hase S, Komoike Y, Takeuchi K
Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan.
Aliment Pharmacol Ther. 2002 Apr;16 Suppl 2:90-101. doi: 10.1046/j.1365-2036.16.s2.22.x.
A recent study demonstrated that inhibition of both cyclooxygenase (COX)-1 and COX-2 is required for the development of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric lesions. However, the role of COX-1 or COX-2 inhibition in the pathogenisis of these lesions remains unclear.
To examine the gastric ulcerogenic properties of selective COX-1 and COX-2 inhibitors in rats and to investigate further the relationship of COX inhibition to various events involved in the process of NSAID-induced gastric lesions.
Animals were given various COX inhibitors p.o., either alone or in combination, and killed 8 h later. Under the treatment, gastric damage, prostaglandin (PG) E2 content, mucosal permeability, myeloperoxidase (MPO) activity as well as gastric motility were examined.
The nonselective COX inhibitor indomethacin inhibited PGE2 production, enhanced gastric motility, and provoked severe lesions in the stomach, with an increase in mucosal permeability and MPO activity. In contrast, the selective COX-2 inhibitor rofecoxib did not induce any damage in the stomach and had no effect on mucosal PGE2 content. Similarly, the selective COX-1 inhibitor SC-560 also caused no gastric damage, despite inhibiting PGE2 production. The combined administration of SC-560 and rofecoxib, however, provoked gross damage in the gastric mucosa, in a dose-dependent manner for each drug. SC-560, but not rofecoxib, caused marked gastric hypermotility and an increase in mucosal permeability, although an increase in MPO activity was observed only when rofecoxib was coadministered. The normal gastric mucosa expressed COX-1 mRNA and not COX-2 mRNA, but COX-2 mRNA was expressed in the stomach after administration of SC-560 as well as indomethacin but not rofecoxib.
These results suggest that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by COX-1 inhibition, but require the inhibition of both COX-1 and COX-2. The inhibition of COX-1 up- regulates COX-2 expression, and COX-2/PGs may, in turn, counteract the deleterious affects of gastric hypermotility due to COX-1 inhibition.
最近一项研究表明，非甾体抗炎药（NSAID）诱导的胃损伤的发生需要同时抑制环氧化酶（COX）-1和COX-2。然而，COX-1或COX-2抑制在这些损伤发病机制中的作用仍不清楚。
研究选择性COX-1和COX-2抑制剂在大鼠中的致胃溃疡特性，并进一步探讨COX抑制与NSAID诱导的胃损伤过程中各种事件的关系。
给动物口服各种COX抑制剂，单独或联合使用，8小时后处死。在治疗过程中，检测胃损伤、前列腺素（PG）E2含量、黏膜通透性、髓过氧化物酶（MPO）活性以及胃动力。
非选择性COX抑制剂吲哚美辛抑制PGE2生成，增强胃动力，并引发严重的胃损伤，同时黏膜通透性和MPO活性增加。相比之下，选择性COX-2抑制剂罗非昔布未引起胃损伤，对黏膜PGE2含量也无影响。同样，选择性COX-1抑制剂SC-560尽管抑制了PGE2生成，但也未引起胃损伤。然而，联合给予SC-560和罗非昔布会引起胃黏膜的严重损伤，且每种药物的损伤程度呈剂量依赖性。SC-560而非罗非昔布引起明显的胃动力亢进和黏膜通透性增加，尽管仅在联合使用罗非昔布时观察到MPO活性增加。正常胃黏膜表达COX-1 mRNA而不表达COX-2 mRNA，但在给予SC-560以及吲哚美辛后胃中表达COX-2 mRNA，而给予罗非昔布后不表达。
这些结果表明，NSAIDs的致胃溃疡特性并非仅由COX-1抑制引起，而是需要同时抑制COX-1和COX-2。COX-1的抑制会上调COX-2的表达，而COX-2/PGs可能反过来抵消由于COX-1抑制引起的胃动力亢进的有害影响。
