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

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