Jiang Q, Engelhardt J F
Department of Anatomy and Cell Biology, University of Iowa School of Medicine, Iowa City 52242, USA.
Eur J Hum Genet. 1998 Jan;6(1):12-31. doi: 10.1038/sj.ejhg.5200158.
Cystic fibrosis (CF) has become a paradigm disorder for the clinical testing of gene therapies in the treatment of inherited disease. In recent years, efforts directed at gene therapy of CF have concentrated on improving gene delivery systems to the airway. Surrogate endpoints for complementation of CFTR dysfunction in the lung have been primarily dependent on correction of chloride transport abnormalities. However, it is now clear that the pathophysiology of CF airways disease is far more complex than can be solely attributed to altered chloride permeability. For example, in addition to functioning as a chloride channel, CFTR also has been implicated in the regulation of other apical membrane conductance pathways through interactions with the amiloride sensitive epithelial sodium channel (ENaC) and the outwardly rectifying chloride channel (ORCC). Superimposed on this functional diversity of CFTR is a highly regulated pattern of CFTR expression in the lung. This heterogeneity occurs at both the level of CFTR protein expression within different cell types in the airway and the anatomical location of these cells in the lung. Potential targets for gene therapy of CF include ciliated, non-ciliated, and goblet cells in the surface airway epithelium as well as submucosal glands within the interstitium of the airways. Each of these distinct cellular compartments may have functionally distinct roles in processes which affect the pathogenesis of CF airways disease, such as fluid and electrolyte balance. However, it is presently unclear which of these cellular targets are most pathophysiologic relevant with regard to gene therapy. Elucidation of the underlying mechanisms of CFTR function in the airway will allow for the rational design of gene therapy approaches for CF lung diseases. This review will provide a summary of the field's current knowledge regarding CFTR functional diversity in the airway and the implications of such diversity for gene therapies of CF lung disease.
囊性纤维化（CF）已成为遗传性疾病基因治疗临床测试的范例性疾病。近年来，针对CF基因治疗的努力主要集中在改进气道基因递送系统。肺部CFTR功能障碍互补的替代终点主要依赖于纠正氯离子转运异常。然而，现在很清楚，CF气道疾病的病理生理学远比仅归因于氯离子通透性改变要复杂得多。例如，除了作为氯离子通道发挥作用外，CFTR还通过与氨氯地平敏感的上皮钠通道（ENaC）和外向整流氯离子通道（ORCC）相互作用，参与调节其他顶端膜电导途径。叠加在CFTR这种功能多样性之上的是其在肺部高度调控的表达模式。这种异质性发生在气道不同细胞类型内CFTR蛋白表达水平以及这些细胞在肺部的解剖位置两个层面。CF基因治疗的潜在靶点包括气道表面上皮中的纤毛细胞、非纤毛细胞和杯状细胞，以及气道间质内的黏膜下腺。这些不同的细胞区室在影响CF气道疾病发病机制的过程中，如液体和电解质平衡，可能各自具有功能上不同的作用。然而，目前尚不清楚这些细胞靶点中哪些对于基因治疗在病理生理学上最为相关。阐明CFTR在气道中的功能潜在机制将有助于合理设计针对CF肺部疾病的基因治疗方法。本综述将总结该领域目前关于CFTR在气道中功能多样性的知识，以及这种多样性对CF肺部疾病基因治疗的影响。
