title: Overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury.
abstract: OBJECTIVE
  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.
authors.affiliation: Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hassett
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Curley
authors.forename: Maya
authors.initials: M
authors.lastname: Contreras
authors.forename: Claire
authors.initials: C
authors.lastname: Masterson
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Higgins
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D000818:Animals; D004731:Endotoxins / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis*
chemical_list: D004731:Endotoxins; D013482:Superoxide Dismutase