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Published Online: 20 March 2008

Gene Therapy for Oxidant Injury-Related Diseases: Adenovirus-Mediated Transfer of Superoxide Dismutase and Catalase cDNAs Protects against Hyperoxia but Not Against Ischemia–Reperfusion Lung Injury

Publication: Human Gene Therapy
Volume 9, Issue Number 10

ABSTRACT

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 intratracheally with an adenovirus (Ad) vector encoding human superoxide dismutase (CuZn-SOD) or catalase cDNA, a mixture of both Ad vectors, or a control Ad vector containing no exogenous gene. Expression of human catalase and CuZn-SOD was demonstrated 3 days later in distal lung epithelial cells and alveolar macrophages, using ELISA and immunochemistry. After exposure to 100% O2 for 62 hr, survival was greater in rats injected with the catalase and/or SOD Ad vectors than in control rats. Ischemia–reperfusion injury was evaluated in the isolated perfused lung model. Overexpression of SOD worsened ischemia-reperfusion injury. Interestingly, concomitant overexpression of catalase prevented this adverse 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 O2 toxicity. Absence of protection against ischemia–reperfusion using intratracheal Ad injections may be related to the lack of endothelial protection, despite epithelial expression of catalase and SOD.

Overview summary

In the healthy lung, the oxidant burden is balanced by the local antioxidant defenses. However, an increased oxidant burden such as hyperoxia or ischemia–reperfusion syndrome may reverse the physiologic oxidant-antioxidant balance in favor of oxidants, leading to lung injury. Using adenovirus-mediated gene transfer to lung epithelium of antioxidant genes, driven by viral promoters, we demonstrated that overexpression of both catalase and CuZn superoxide dismutase in lung epithelial cells and alveolar macrophages increased rat survival under 100% hyperoxia, but did not protect against ischemia–reperfusion syndrome.

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Published In

cover image Human Gene Therapy
Human Gene Therapy
Volume 9Issue Number 10July 1998
Pages: 1487 - 1496
PubMed: 9681420

History

Published online: 20 March 2008
Published in print: July 1998
Accepted: 20 April 1998
Received: 6 January 1998

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1Université René Descartes, Hôpital Laënnec, Paris, France. 2Cleveland Clinic Foundation, Cleveland, OH. 3Laboratoire de Chirurgie Expérimental, Hôpital Marie-Lannelongue, Le Plessis Robinson, France. 4Pulmonary-Critical Care Medicine Branch, NHLBI, NIH, Bethesda, MD. 5Cornell University Medical College, New York, NY. 6INSERM U25, F-75730 Paris cedex 15, France.

Notes

Address reprint requests to: Dr. Patricia Lemarchand, INSERM U25, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, F-75730 Paris cedex 15, France

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