Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Japan.
J Pharmacol Sci. 2009 Dec;111(4):352-60. doi: 10.1254/jphs.09169fp. Epub 2009 Nov 27.
NADPH oxidase is an enzyme that converts molecular oxygen into reactive oxygen species, which cause severe damage in several organs. Cyclooxygenase (COX)-2 is an inducible enzyme that is important in gastric mucosal defense and repair processes. It is unclear whether NADPH oxidase is related to COX expression in the gastric mucosa, so we investigated the correlation. Under urethane anesthesia, a male Sprague Dawley rat stomach was mounted in an ex-vivo chamber, and ischemia/reperfusion (I/R) was performed through a cannula in the femoral vein. I/R significantly increased NADPH oxidase activity, H(2)O(2) production, and myeloperoxidase (MPO) activity. In contrast, ischemia alone clearly enhanced both NADPH oxidase activity and H(2)O(2) production but not MPO activity. Pretreatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI) suppressed I/R-induced mucosal damage. On the other hand, the selective COX-2 inhibitor rofecoxib exhibited a tendency to enhance the severity of gastric damage induced by I/R, although the selective COX-1 inhibitor SC-560 and the nonselective COX inhibitor indomethacin had no effect. I/R also increased the expression of COX-2, and this increase was suppressed by pretreatment with DPI. These findings suggest that the increase in NADPH oxidase activity is involved in the occurrence of gastric mucosal damage induced by I/R and that this enzyme activity may be causally related to the upregulation of COX-2 during I/R.
NADPH 氧化酶是一种将分子氧转化为活性氧物质的酶，这种物质会导致多个器官严重损伤。环氧化酶（COX）-2 是一种诱导酶，在胃黏膜防御和修复过程中非常重要。目前尚不清楚 NADPH 氧化酶是否与胃黏膜中的 COX 表达有关，因此我们进行了相关研究。在氨基甲酸乙酯麻醉下，将雄性 Sprague Dawley 大鼠的胃装入离体腔室，通过股静脉中的套管进行缺血/再灌注（I/R）。I/R 显著增加了 NADPH 氧化酶活性、H2O2 生成和髓过氧化物酶（MPO）活性。相比之下，单独缺血明显增强了 NADPH 氧化酶活性和 H2O2 生成，但不增强 MPO 活性。NADPH 氧化酶抑制剂二苯基碘（DPI）预处理抑制了 I/R 诱导的黏膜损伤。另一方面，选择性 COX-2 抑制剂罗非昔布（rofecoxib）表现出增强 I/R 诱导的胃损伤严重程度的趋势，尽管选择性 COX-1 抑制剂 SC-560 和非选择性 COX 抑制剂吲哚美辛没有这种作用。I/R 还增加了 COX-2 的表达，而 DPI 的预处理抑制了这种增加。这些发现表明，NADPH 氧化酶活性的增加与 I/R 诱导的胃黏膜损伤的发生有关，并且这种酶活性可能与 I/R 期间 COX-2 的上调有关。
