Xenograft Model of the CF Airway

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in defective ion transport, leading to thick mucus, impaired mucociliary clearance and decreased bacterial killing in the lung (,). Despite recent progress in associating cystic fibrosis (CF) defects with CFTR dysfunction, there are many unanswered questions concerning the roles of CFTR in both normal airway biology and in CF pathology. Before effective therapeutic approaches for CF lung disease will be realized, several remaining challenges must first be overcome. These include a more precise definition of CFTR functions in fluid transport, electrolyte balance, and in the regulation of other epithelial ion channels. Moreover, the heterogeneity of CFTR expression among different cell types and regions of the lung necessitates the identification of pathophysiologic relevant cellular targets for gene therapy approaches for CF. For example, submucosal glands (SMGs) secrete mucous, airway surface fluid, and bactericidal proteins, and are a predominant site of CFTR-expressing cells in the lung. In contrast, cells in the surface airway epithelium show lower levels of CFTR expression (). The importance of SMGs in the pathoprogression of CF lung disease is still an open question. Hindering a firm answer to this question is a lack of animal models that mimic human CF airways disease at the molecular level and cellular levels.