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在囊性纤维化小鼠中,降低NHE3介导的Na⁺吸收可提高生存率并降低肠梗阻的发生率。

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice.

作者信息

Bradford Emily M, Sartor Maureen A, Gawenis Lara R, Clarke Lane L, Shull Gary E

机构信息

Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML0524, Cincinnati, OH 45267-0524, USA.

出版信息

Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G886-98. doi: 10.1152/ajpgi.90520.2008. Epub 2009 Jan 22.

Abstract

In cystic fibrosis, impaired secretion resulting from loss of activity of the cystic fibrosis transmembrane conductance regulator (CFTR) causes dehydration of intestinal contents and life-threatening obstructions. Conversely, impaired absorption resulting from loss of the NHE3 Na+/H+ exchanger causes increased fluidity of the intestinal contents and diarrhea. To test the hypothesis that reduced NHE3-mediated absorption could increase survival and prevent some of the intestinal pathologies of cystic fibrosis, Cftr/Nhe3 double heterozygous mice were mated and their offspring analyzed. Cftr-null mice lacking one or both copies of the NHE3 gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival. Goblet cell hyperplasia was eliminated, but not the accumulation of Paneth cell granules or increased cell proliferation in the crypts. Microarray analysis of small intestine RNA from Cftr-null, NHE3-null, and double-null mice all revealed downregulation of genes involved in xenobiotic metabolism, including a cohort of genes involved in glutathione metabolism. Expression of energy metabolism genes was altered, but there were no changes in genes involved in inflammation. Total intracellular glutathione was increased in the jejunum of all of the mutants and the ratio of reduced to oxidized glutathione was reduced in Cftr-null mutants, indicating that CFTR deficiency affects intestinal glutathione metabolism. The data establish a major role for NHE3 in regulating the fluidity of the intestinal contents and show that reduced NHE3-mediated absorption reverses some of the intestinal pathologies of cystic fibrosis, thus suggesting that it may serve as a potential therapeutic target.

摘要

在囊性纤维化中,囊性纤维化跨膜传导调节因子(CFTR)活性丧失导致的分泌受损会引起肠内容物脱水和危及生命的梗阻。相反,NHE3钠/氢交换体丧失导致的吸收受损会使肠内容物流动性增加并引发腹泻。为了验证NHE3介导的吸收减少可提高存活率并预防囊性纤维化的一些肠道病变这一假说,将Cftr/Nhe3双杂合小鼠进行交配,并对其后代进行分析。缺乏一个或两个NHE3基因拷贝的Cftr基因敲除小鼠的肠内容物流动性增加,这防止了梗阻的形成并提高了存活率。杯状细胞增生消失了,但潘氏细胞颗粒的积累或隐窝中细胞增殖增加并未消失。对Cftr基因敲除、NHE3基因敲除和双基因敲除小鼠小肠RNA的微阵列分析均显示,参与外源性物质代谢的基因下调,包括一组参与谷胱甘肽代谢的基因。能量代谢基因的表达发生了改变,但参与炎症的基因没有变化。所有突变体空肠中的总细胞内谷胱甘肽增加,而Cftr基因敲除突变体中还原型谷胱甘肽与氧化型谷胱甘肽的比例降低,这表明CFTR缺乏会影响肠道谷胱甘肽代谢。这些数据确立了NHE3在调节肠内容物流动性方面的主要作用,并表明NHE3介导的吸收减少可逆转囊性纤维化的一些肠道病变,因此提示它可能是一个潜在的治疗靶点。

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