GENE-THERAPY FOR OXIDANT INJURY-RELATED DISEASES - ADENOVIRUS-MEDIATED TRANSFER OF SUPEROXIDE-DISMUTASE AND CATALASE CDNAS PROTECTS AGAINSTHYPEROXIA BUT NOT AGAINST ISCHEMIA-REPERFUSION LUNG INJURY

Hyperoxia and ischemia-reperfusion cause profound lung cellular damage mediated, in part, by generation of oxygen radicals. We hypothesized that gene therapy can be used to overcome oxidant injury by augmenting intracellular antioxidant enzymes, Adult rats were injected intratrac heally with an adenovirus (Ad) vector encoding human superoxide dismut ase (CuZn-SOD) or catalase cDNA, a mixture of both Ad vectors, or a co ntrol Ad vector containing no exogenous gene. Expression of human cata lase and CuZn-SOD was demonstrated 3 days later in distal lung epithel ial cells and alveolar macrophages, using ELISA and immunochemistry, A fter exposure to 100% O-2 for 62 hr, survival was greater in rats inje cted with the catalase and/or SOD Ad vectors than in control rats. Isc hemia-reperfusion injury was evaluated in the isolated perfused lung m odel. Overexpression of SOD worsened ischemia-reperfusion injury. Inte restingly, concomitant overexpression of catalase prevented this adver se effect, but did not protect against ischemia-reperfusion injury. We conclude that Ad-mediated transfer to lungs of both catalase and SOD cDNAs protects from pulmonary O-2 toxicity. Absence of protection agai nst ischemia-reperfusion using intratracheal Ad injections may be rela ted to the lack of endothelial protection, despite epithelial expressi on of catalase and SOD.