Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene.
A recombinant prostaglandin G/H (PGH) synthase gene has been expressed in vitro in bovine pulmonary artery endothelial cells and in vivo in rabbits by transfection with a plasmid using cationic liposomes. Transfection of bovine pulmonary artery endothelial cells with the PGH synthase cDNA resulted in increased intracellular PGH synthase protein (determined by Western blot analysis) and increased release of prostacyclin. Rabbits intravenously transfected with the PGH synthase gene had increased plasma levels of prostacyclin and PGE2, and their lungs produced increased amounts of the same eicosanoids. In an in situ, perfused preparation of PGH synthase transfected rabbit lungs, the pressor response to endotoxin was markedly attenuated. In addition, pulmonary edema and release of thromboxane B2 into the perfusate after endotoxin infusion were markedly decreased in transfected lungs compared to controls (animals transfected with a pCMV4 construct that did not contain a cDNA insert). The data suggest that augmented endogenous production of prostacyclin and PGE2, achieved by liposome-mediated gene transfer, protects the lungs from endotoxin. This may be caused in part by suppression of endotoxin-stimulated thromboxane B2 production. Modification of lipid mediator responses by in vivo transfection is a potential approach to the therapy of acute lung injury.
Conary
J T
JT
Center for Lung Research, Vanderbilt University, Nashville, Tennessee 37232-2650.
Parker
R E
RE
Christman
B W
BW
Faulks
R D
RD
King
G A
GA
Meyrick
B O
BO
Brigham
K L
KL
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000378:metabolism; D015316:Genetic Therapy; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011817:Rabbits; D014162:Transfection
D008070:Lipopolysaccharides; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone