Gene therapy in lung transplantation: Effective gene transfer via the airways

Objectives: Gene therapy may provide a means of modifying factors that contribute to the development of pathologic processes in transplanted lungs, Experiments were designed to study the feasibility of adenovirus-mediated gene transfer by way of the airways to the transplanted lung, Methods: Orthotopic left lung transplantation (Lewis to Lewis rats) was performed on four groups of animals, 300 mu l of adenovirus solution encoding for beta-galactosidase was infused into the left bronchus of donor rats at viral concentrations of 10(8) pfu/ml (n = 5), 10(9) pfu/ml (n = 6), and 10(10) pfu/ml (n = 6), and the lung was ventilated for 5 minutes, Controls (n = 6) received medium only, Seven days after transplantation, native and transduced, transplanted lungs were harvested, Sections of lung were fixed and stained with a solution of X-Gal (5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) and staining was evaluated for distribution by cell type and intensity, Results: beta-Galactosidase expression was absent in the control group and in the native lunes, Two of five lungs in the 10(8) group expressed beta-galactosidase, but in a limited distribution and intensity. All six lungs in the 10(9) group and five of sis lungs in the 10(10) group expressed beta-galactosidase, The distribution and intensity of beta-galactosidase expression ranged from only a few cells staining per slide to up to 75%, Pneumocytes were the most frequently stained cell type followed by alveolar macrophages. Conclusions: Gene transfer to the transplanted lung via the bronchial route is feasible and offers a novel technique to modify pathologic processes in the transplanted lung.