Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
J Pharmacol Exp Ther. 2010 Apr;333(1):91-8. doi: 10.1124/jpet.109.162578. Epub 2009 Dec 30.
We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.
我们研究了半胱氨酰白三烯（CysLTs）在小鼠缺血再灌注（I/R）性胃溃疡反应中的作用。实验在禁食 18 小时后的雄性 C57BL/6J 小鼠中进行。在氨基甲酸乙酯麻醉下，夹闭腹腔动脉 30 分钟，然后通过移除夹子实现再灌注。此后 60 分钟检查胃病变。普仑司特（CysLT 受体 1（CysLT（1）R）拮抗剂）和 1-[[5'-(3''-甲氧基-4''-乙氧羰基-氧代苯)-2',4'-戊二烯酰]氨基乙基]-4-二苯甲氧基哌啶[TMK688；5-脂氧合酶（5-LOX）抑制剂]的预先给药可减轻 I/R 诱导的胃损伤的严重程度。相反，吲哚美辛预处理会显著加重这些损伤，而 TMK688 或普仑司特的共同给药则消除了这种反应。I/R 后胃中 CysLT（1）R 的基因表达上调，但吲哚美辛存在时 I/R 下两种表达均增加。I/R 轻度增加胃黏膜 CysLT 含量，但当动物用吲哚美辛预处理时，这种增加明显增强。TMK688 减弱了 I/R 期间吲哚美辛对 CysLT 生物合成反应的增强。吲哚美辛本身可引起胃 CysLT（1）R 表达略有增加，并明显上调 5-LOX 表达。我们得出结论，I/R 上调胃中 CysLT（1）R 的表达；CysLTs 通过激活 CysLT（1）R 在 I/R 诱导的胃损伤发病机制中发挥作用；吲哚美辛加重这些病变可能是由于 CysLT 产生增加和 5-LOX 表达上调，以及前列腺素产生减少所致。
