DECREASED EXPRESSION OF THE CFTR PROTEIN IN REMODELED HUMAN NASAL EPITHELIUM FROM NON-CYSTIC FIBROSIS PATIENTS

BACKGROUND: In normal adult pseudostratified human nasal surface epith elium, the cystic fibrosis transmembrane conductance regulator (CFTR) is localized to the apical domain of the ciliated cells, whereas in cy stic fibrosis (CF), the mutated Delta F 508 CFTR exhibits an abnormal cytoplasmic localization. Frequent airway injuries either in CF or non -CF patients may induce a remodeling of the surface epithelium charact erized by a change in the morphological structure from normal columnar pseudostratified epithelium to either basal cell hyperplasia, mucous cell hyperplasia, or squamous metaplasia. EXPERIMENTAL DESIGN: The loc alization of CFTR parallel to markers of cell differentiation, such as cytokeratin 14 (CK14, a marker of basal cells), cytokeratin 18 (CK 18 , a marker of ciliated and mucous cells), cytokeratin 13 (CK13, a mark er of squamous metaplasia cells), and desmoplakins (DP) 1 and 2 (marke rs of desmosomes) was analyzed by indirect immunofluorescence. RESULTS : In normal pseudostratified epithelium, CFTR was detected at the apic al plasma membrane of the ciliated cells, CK14 was identified in basal cells of focal areas, CK18 was localized in both ciliated and mucous cells, CK 13 was detected in all basal cells, and DP 1 and 2 were pref erentially detected at the interface between columnar and basal cells. In basal cell hyperplasia, CFTR was poorly expressed in the cytoplasm of the more superficial cells, CK14 and CK13 were localized in basal cell multilayers, CK18 labeling was present in the more superficial ce ll layers, and DP 1 and 2 were preferentially detected at the interfac e between the more basal cells. In squamous metaplasia, CFTR labeling was either very low or even undetectable, CK14 was found in focal area s of the more basal cell layers, CK18 labeling was either very low or undetectable, CK13 expression was restricted to the flattened cells to ward the epithelial surface, and DP 1&2 were intensively present betwe en all the epithelial cells. CONCLUSIONS: These results suggest that t he localization of CFTR in human nasal surface epithelium is related t o the differentiation state of this epithelium. Abnormally low express ion of the CFTR protein may not only be caused by CFTR gene mutations but can also be associated with airway surface epithelium dedifferenti ation and remodeling.