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. Trans fection of bovine pulmonary artery endothelial cells with the PGH synt hase cDNA resulted in increased intracellular PGH synthase protein (de termined by Western blot analysis) and increased release of prostacycl in. Rabbits intravenously transfected with the PGH synthase gene had i ncreased plasma levels of prostacyclin and PGE(2) and their lungs prod uced increased amounts of the same eicosanoids. In an in situ, perfuse d preparation of PGH synthase transfected rabbit lungs, the presser re sponse to endotoxin was markedly attenuated. In addition, pulmonary ed ema and release of thromboxane B-2 into the perfusate after endotoxin infusion were markedly decreased in transfected lungs compared to cont rols (animals transfected with a pCMV4 construct that did not contain a cDNA insert). The data suggest that augmented endogenous production of prostacyclin and PGE(2), achieved by liposome-mediated gene transfe r, protects the lungs from endotoxin. This may be caused in part by su ppression of endotoxin-stimulated thromboxane B-2 production. Modifica tion of lipid mediator responses by in vivo transfection is a potentia l approach to the therapy of acute lung injury.