IN-VIVO ADENOVIRUS-MEDIATED GENE-TRANSFER TO LUNGS VIA PULMONARY-ARTERY

On the basis of the knowledge that the pulmonary and bronchial circula tions have extensive anastomoses, we hypothesized that gene transfer t o the endothelium of both pulmonary and bronchial circulations might b e achieved with replication-deficient recombinant adenovirus (Ad) vect ors administered to the pulmonary circulation. To evaluate this concep t, the right upper lobe branches of the sheep pulmonary artery and vei n were temporarily occluded and a replication-deficient recombinant Ad vector containing the Escherichia coli lacZ reporter gene coding for beta-galactosidase (beta-Gal) was infused into the lumen of the occlud ed pulmonary artery. After 15 min, the pulmonary circulation was resto red, and 1 or 4 days later the lungs were evaluated by histochemical a nalysis for beta-Gal activity. Gene transfer and expression were posit ive in 13 of 17 evaluated sheep. No beta-Gal activity was detected in any category of cells of uninfected lobes. As hypothesized, beta-Gal a ctivity was detected in endothelial cells of the right upper lobe pulm onary and bronchial circulations. Unexpectedly, gene transfer was also observed in epithelial cells of the alveoli and the airways (bronchi and bronchioles) as well as in the epithelium of submucosal glands. Th ese studies demonstrate that it is possible to use Ad vectors for tran sfer and expression of genes to lung parenchymal cells served by both the pulmonary and bronchial circulations. Furthermore, whereas adminis tration of such vectors via the airways results in gene transfer only to the epithelium, pulmonary artery administration permits gene transf er to both endothelium and epithelium, thus expanding the target range of Ad gene transfer to the lungs.