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: Junji Ueda, Marlene E Starr, Hitoshi Takahashi, Jie Du, Ling Yi Chang, James D Crapo, B Mark Evers, Hiroshi Saito
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 45 Issue 6 Pg. 897-904 (Sep 15 2008) ISSN: 0891-5849 [Print] United States
• PMID: 18640266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Primers
• Lipopolysaccharides
• Superoxide Dismutase

Topics

• Animals
• Base Sequence
• Blotting, Northern
• DNA Primers
• Dose-Response Relationship, Drug
• Down-Regulation
• Extracellular Space (enzymology)
• Inflammation (chemically induced, metabolism)
• Lipopolysaccharides (toxicity)
• Lung (enzymology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Superoxide Dismutase (genetics, metabolism)
• Transcription, Genetic