CELL-PROLIFERATION IN BRONCHIAL EPITHELIUM AND SUBMUCOSAL GLANDS OF CYSTIC-FIBROSIS PATIENTS

Integrative gene therapy typically requires dividing cells. This requi rement has been perceived as an impediment for gene transfer to mature , uninjured airways where proliferation rates are very low. In disease s such as cystic fibrosis (CF) that may be candidates for integrative gene therapy, airway cell turnover is not known but may be increased a s a result of chronic inflammation. To determine if cells in airway su rface epithelium and submucosal glands of CF patients proliferate at a n increased rate, paraffin sections of bronchial segments removed from CF patients (n = 6) at the time of lung transplantation or rapid auto psy and from non-CF patients (n = 4) undergoing lung resection or tran splantation were immunostained with PC10, a monoclonal antibody to pro liferating cell nuclear antigen (PCNA), a marker of proliferating cell s. The PCNA index (percentage of nuclei immunostaining for PCNA) in CF bronchial surface epithelium was 17.0 +/- 4.6% (mean +/- SEM), substa ntially greater than in non-CF airways (< 0.2%). Within submucosal gla nds, PCNA-positive cells were more prevalent in the collecting ducts o f CF patients than in those of normal subjects, but only rare mucous o r serous cells were PCNA positive. These studies show that airway epit helial cell proliferation rates can be very high in inflamed CF airway s. This prevalence of proliferating cells suggests that CF airway epit helium and submucosal gland ducts may be amenable to gene transfer usi ng vectors, such as retroviruses, that require cell replication for st able integrative expression. Further studies are needed to evaluate ce ll proliferation in CF airways with less extensive airway injury.