Peer-Reviewed Journal Details
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Hassett P, Curley GF, Contreras M, Masterson C, Higgins BD, O'Brien T, Devaney J, O'Toole D, Laffey JG.
Intensive Care Medicine
Overexpression of pulmonary extracellular uperoxide dismutase attenuates endotoxin induced acute lung injury
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PURPOSE: Superoxide is produced by activated neutrophils during the inflammatory response to stimuli such as endotoxin, can directly or indirectly injure host cells, and has been implicated in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We wished to determine the potential for pulmonary overexpression of the extracellular isoform of superoxide dismutase (EC-SOD) to reduce the severity of endotoxin-induced lung injury.METHODS: Animals were randomly allocated to undergo intratracheal instillation of (1) surfactant alone (vehicle); (2) adeno-associated virus (AAV) vectors containing a null transgene (AAV-null); and (3) adeno-associated virus vectors containing the EC-SOD transgene (AAV-EC-SOD) and endotoxin was subsequently administered intratracheally. Two additional groups were randomized to receive (1) vehicle or (2) AAV-EC-SOD, and to undergo sham (vehicle) injury. The severity of the lung injury was assessed in all animals 24 h later.RESULTS: Endotoxin produced a severe lung injury compared to sham injury. The AAV vector encoding EC-SOD increased lung EC-SOD concentrations, and enhanced the antioxidant capacity of the lung. EC-SOD overexpression decreased the severity of endotoxin-induced ALI, reducing the decrement in systemic oxygenation and lung compliance, decreasing lung permeability and decreasing histologic injury. EC-SOD attenuated pulmonary inflammation, decreased bronchoalveolar lavage neutrophil counts, and reduced interleukin-6 and CINC-1 concentrations. The AAV vector itself did not contribute to inflammation or to lung injury.CONCLUSIONS: Pulmonary overexpression of EC-SOD protects the lung against endotoxin-induced ALI.
Grant Details
This study was funded by the European Research Council (DOT, JGL), the Association of Anaesthetists of Great Britain and Ireland (JGL, BH) and the Health Research Board, Ireland (JD, BH, JGL). Dr O’Toole is a Research Fellow with the European Research Council (Grant No. ERC-2007-StG 207777) and Dr Devaney is a postdoctoral fellow with the Health Research Board, Ireland (Grant No. RP/2008/193).
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