title: Decreased pulmonary extracellular superoxide dismutase during systemic inflammation.
abstract: Oxidative damage is a major cause of lung injury during systemic inflammatory response syndrome. In this study, the expression of an antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), and its protective role against pulmonary oxidative damage were investigated using mouse models of systemic inflammation. Intraperitoneal injection with bacterial endotoxin lipopolysaccharides (LPS; 20 mg/kg) caused oxidative damage in lungs as assessed by increased tyrosine nitration in proteins. LPS administration also resulted in a rapid and significant loss of more than 80% of pulmonary EC-SOD in a time- and dose-dependent manner, but other types of SODs, cytoplasmic CuZn-SOD and mitochondrial Mn-SOD, were not affected. EC-SOD protein is most abundant in lungs but also present at high levels in other tissues such as heart and white fat; however, the LPS-mediated decrease in this enzyme was most apparent in the lungs. Intravenous injection of mice with tumor necrosis factor alpha (10 microg per mouse) also caused a 60% decrease in EC-SOD in the lungs, suggesting that the EC-SOD down-regulation is mediated by this LPS-inducible inflammatory cytokine. A protective role for EC-SOD against LPS-mediated systemic inflammation was shown by an increased survival rate (75% vs 29% in 5 days) and decreased pulmonary oxidative damage in EC-SOD transgenic mice that overexpress the human EC-SOD gene. These results demonstrate that the inflammation-mediated EC-SOD down-regulation has a major pathophysiological impact during the systemic inflammatory response syndrome.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Junji
authors.initials: J
authors.lastname: Ueda
authors.forename: Marlene E
authors.initials: ME
authors.lastname: Starr
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Ling Yi
authors.initials: LY
authors.lastname: Chang
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005110:Extracellular Space / Q000201:enzymology*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D008070:Lipopolysaccharides; D013482:Superoxide Dismutase