Catheter-mediated pulmonary vascular gene transfer and expression.
The study and treatment of pulmonary diseases may be greatly facilitated by in vivo expression of specific recombinant genes in the pulmonary vasculature and lung parenchyma. To evaluate the feasibility of gene transfer to the pulmonary vasculature, cationic liposomes and adenoviral vectors encoding a human placental alkaline phosphatase (hpAP) gene were delivered into a pulmonary artery of 24 pigs by percutaneous right heart catheterization. Pulmonary tissue was harvested within 20 minutes or 5, 14, or 28 days later and was analyzed for gene transfer and expression. Five days after exposure to liposomes or adenoviral vectors, transfer of DNA and expression of mRNA were demonstrated in transfected lung tissue. Recombinant alkaline phosphatase protein was observed in both the vasculature and in alveolar septa but not in the bronchi. Expression of hpAP protein was observed at 5 days, was diminished at 14 days, and was absent 28 days after gene transfer with both liposome and adenoviral vectors. No major adverse effects of gene expression were detected by histological examination of the transfected lung segments compared with control segments. Gene transfer to the lung by either vector was not associated with significant biochemical abnormalities or histological changes 5, 14, or 28 days later in other organs, including carotid artery, heart, liver, spleen, kidney, skeletal muscle, ovary, and testes. These studies demonstrate that after intravascular gene delivery to the lung, recombinant genes are expressed in the vasculature and alveoli. This approach may provide a useful model for the experimental study of pulmonary vascular diseases, including pulmonary fibrosis and pulmonary thrombosis disorders.
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0022.
D W
DW
Muller
D
D
Gordon
H
H
San
Z
Z
Yang
V J
VJ
Pompili
G J
GJ
Nabel
E G
EG
Nabel
D000256:Adenoviridae; D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D006328:Cardiac Catheterization; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006651:Histocytochemistry; D006801:Humans; D008081:Liposomes; D008168:Lung / Q000166:cytology / Q000473:pathology; D010920:Placenta / Q000201:enzymology; D011650:Pulmonary Alveoli / Q000166:cytology; D011651:Pulmonary Artery / Q000166:cytology / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection
D008081:Liposomes; D012333:RNA, Messenger; D000469:Alkaline Phosphatase