Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis
Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis
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DOI：
10.1152/ajpgi.00015.2002
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发表时间：
2002-07-01
影响因子：
4.5
通讯作者：
Haskó, G
中科院分区：
文献类型：
--
作者：
Németh, ZH;Deitch, EA;Haskó, G
Na+/H+交换器(NHEs)是存在于所有哺乳动物细胞中的完整跨膜蛋白。有大量证据表明，NHEs调节炎症过程。由于肠上皮细胞表达多种NHEs，我们测试了NHEs也参与调节上皮细胞炎症反应的可能性。此外，由于上皮炎性反应是炎症性肠病(IBD)黏膜炎症的重要因素，我们在IBD小鼠模型中研究了NHEs在疾病活动调节中的作用。在人的肠上皮细胞中，使用多种药物抑制NHE，包括阿米洛利、5-(N-甲基-N-异丁基)阿米洛利、5-(N-乙基-N-异丙基)阿米洛利、三尖杉酯碱、可乐定和西咪替丁，可抑制白细胞介素8(IL-8)的产生。NHE抑制IL-8的作用与其减少IL-8mRNA积聚有关。NHE抑制可抑制p42/p44丝裂原活化蛋白激酶和核因子-kappaB的激活。最后，NHE抑制改善了硫酸葡聚糖治疗的小鼠的IBD病程。我们的数据表明，抑制NHEs可能是一种值得探索的治疗IBD的方法。
Na+/H+ exchangers (NHEs) are integral transmembrane proteins found in all mammalian cells. There is substantial evidence indicating that NHEs regulate inflammatory processes. Because intestinal epithelial cells express a variety of NHEs, we tested the possibility that NHEs are also involved in regulation of the epithelial cell inflammatory response. In addition, since the epithelial inflammatory response is an important contributor to mucosal inflammation in inflammatory bowel disease (IBD), we examined the role of NHEs in the modulation of disease activity in a mouse model of IBD. In human gut epithelial cells, NHE inhibition using a variety of agents, including amiloride, 5-(N-methyl-N-isobutyl) amiloride, 5-(N-ethyl-N-isopropyl) amiloride, harmaline, clonidine, and cimetidine, suppressed interleukin-8 (IL-8) production. The inhibitory effect of NHE inhibition on IL-8 was associated with a decrease in IL-8 mRNA accumulation. NHE inhibition suppressed both activation of the p42/p44 mitogen-activated protein kinase and nuclear factor-kappaB. Finally, NHE inhibition ameliorated the course of IBD in dextran sulfate-treated mice. Our data demonstrate that inhibition of NHEs may be an approach worthy of pursuing for the treatment of IBD.