Department of Pediatrics, Columbia University, New York, New York, USA.
Nat Med. 2012 Apr 5;18(4):509-19. doi: 10.1038/nm.2715.
Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes-airway inflammation and spontaneous infection-may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance.
囊性纤维化跨膜电导调节因子（CFTR）作为一种通道，调节离子和水在上皮屏障中的运输。CFTR 的突变是囊性纤维化临床表现的基础，它会影响肺部的上皮固有免疫功能，导致过度和无效的气道炎症，无法清除肺部病原体。除了过度中性粒细胞募集的影响外，突变的 CFTR 通道不能运输抗氧化剂来抵消中性粒细胞相关的氧化应激。虽然肺外白细胞中突变 CFTR 的表达不会显著损害其功能，但囊性纤维化中气道炎症的预期调节显然存在缺陷。由此产生的细菌感染是由具有大量遗传和代谢灵活性的生物体引起的，它们可以抵抗多类抗生素并逃避吞噬清除。开发近似人类肺部表型（气道炎症和自发性感染）的动物模型，可能为我们提供急需的工具，以确定 CFTR 如何调节黏膜免疫，并直接测试药物增强和纠正突变 CFTR 功能对细菌清除的影响。
