Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion
Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion
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DOI：
10.1172/jci38662
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发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Quinton, Paul M.
中科院分区：
文献类型：
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作者：
Garcia, Mary Abigail S.;Yang, Ning;Quinton, Paul M.
囊性纤维化（CF）中黏液相关病理的机制尚不清楚。然而，最近的研究表明，CF跨膜电导调节剂（CFTR）是碳酸氢盐（HCO3-）运输所必需的，而HCO3-对正常粘液形成至关重要。因此，我们利用小鼠离体小肠研究了HCO3-在粘液分泌中的作用。在HCO3-存在或不存在的情况下，黏液释放的基础速率相似。然而，在没有HCO3-的情况下，PGE(2)或5-羟色胺（5-HT）刺激的粘液释放大约是HCO3-存在时这些分子刺激的一半。抑制HCO3-和液体运输显著减少受刺激的粘液释放。然而，缺乏HCO3-和抑制HCO3-运输都不会影响液体分泌速率，这表明去除HCO3-对粘液释放的影响不是由于液体分泌减少。在CF小鼠模型（小鼠为最常见的人类CFTR突变纯合子）中，在存在或不存在HCO3-的情况下，用PGE2或5-HT刺激肠道粘液释放最小。这些数据表明，正常的粘液释放需要同时分泌HCO3-，在CF患者的粘液分泌器官中观察到的特征性粘液聚集可能是HCO3-运输缺陷的结果。
The mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO3-) transport and that HCO3- is critical for normal mucus formation. We therefore investigated the role of HCO3- in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO3- were similar. However, in the absence of HCO3-, mucus release stimulated by either PGE(2) or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO3-. Inhibition of HCO3- and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO3- nor inhibition of HCO3- transport affected fluid secretion rates, indicating that the effect of HCO3- removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE2 or 5-HT in the presence or absence of HCO3-. These data suggest that normal mucus release requires concurrent HCO3- secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO3- transport.