The anion transport protein Slc26a9 in the bronchial and intestinal epithelium: Physiological functions, pathophysiological relevance, and interaction with the anion channel CFTR

上皮阴离子转运在所有器官的上皮粘膜保护中都起着至关重要的作用。Slc26阴离子转运基因家族有10个成员，在粘膜保护和上皮转运生理中起着重要但尚未完全了解的作用。Slc26a9在胃和肺中高水平表达，其次是十二指肠、肾脏、神经系统和生殖道中的特殊细胞。其输运特性在讨论中存在争议，其生理功能在很大程度上不清楚。最近我们发现，slc26a9缺陷小鼠分泌胃酸的能力降低，胃粘膜发生癌前病变。我们还发现，在支气管内吸入IL-13后，Slc26a9缺陷小鼠不能上调阴离子电导，可能是Slc26a9，并经历支气管粘液堵塞。Slc26a9基因多态性与囊性纤维化患者的胎便性肠梗阻风险增加、精神分裂症患者的神经认知缺陷以及儿童哮喘风险增加相关。因此，我们计划研究Slc26a9在肺和小肠中的生理和病理生理作用，并研究Slc26a9与CFTR的分子相互作用。这些实验将为气道和小肠阴离子、液体和碳酸氢盐分泌的分子调控提供新的见解。它们可能为气道和十二指肠的粘液溶解和粘膜保护物质的新药物开发策略铺平道路，并导致更好地理解上皮疾病（如阻塞性肺病、消化性溃疡和囊性纤维化）的病理生理学。

Epithelial anion transport has turned out to be of paramount importance for epithelial mucosal protection in all organs studied so far. The Slc26 anion transporter gene family with 10 members plays an important but as yet incompletely understood role in mucosal protective and epithelial transport physiology. Slc26a9 is expressed at high levels in the stomach and the lung, followed by the duodenum, specialized cells in the kidney, the neural system and the reproductive tract. Its transport properties are controversially discussed, and its physiological functions are largely unclear. Recently we could show that Slc26a9-deficient mice loose the ability to secrete gastric acid and develop premalignant lesions in the gastric mucosa. We also found that upon intrabronchial inhalation of IL-13, Slc26a9-deficient mice are not able to upregulate an anion conductance, presumably Slc26a9, and experience bronchial mucus plugging. Polymorphisms in the Slc26a9 gene are associated with an increased risk for meconium ileus in cystic fibrosis patients, neurocognitive defects in schizo¬phrenic patients, and increased risk for childhood asthma. Therefore, we plan to investigate the physiological and pathophysiological role of Slc26a9 in the lung and the small intestine, as well as to study the molecular interaction of Slc26a9 with CFTR. These experiments will provide new insight into the molecular regulation of anion-, fluid and bicarbonate secretion in the airways and the small intestine. They may pave the way for novel drug development strategies for mucolytic and mucosal protective substances for the airways and the duodenum, and result in a better under¬standing of the pathophysiology of epithelial diseases such as obstructive lung disease, peptic ulceration and cystic fibrosis.