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 α (10 μg 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.
|Number of pages||8|
|Journal||Free Radical Biology and Medicine|
|State||Published - Sep 15 2008|
Bibliographical noteFunding Information:
The authors thank Karen Martin for manuscript preparation and Tatsuo Uchida for statistical analysis. We also thank Dr. Naseem Ansari at the University of Texas Medical Branch for her thoughtful advice on the analysis of oxidative stress. Dr. James Crapo holds patents on antioxidant mimetic compounds that demonstrate antioxidant activity similar to that of the EC-SOD protein. This work was supported by National Institutes of Health Grant RO1-AG025908.
- Free radicals
- Oxidative stress
- Superoxide dismutase
- Systemic inflammation
ASJC Scopus subject areas
- Physiology (medical)