Extracellular Superoxide Dismutase Attenuates Lung Injury after Hemorrhage

Abstract

Reperfusion of the lung after hemorrhage generates free radicals such as superoxide (O(2)(.)) that may injure the lung; however, the relative importance of intracellular versus extracellular free radicals is unclear. The superoxide dismutases (SOD) are the primary enzymatic method to reduce superoxide. We examined whether lung-specific overexpression of extracellular superoxide dismutase (EC-SOD) would attenuate hemorrhage-induced lung injury. Wild-type mice and mice overexpressing the human EC-SOD gene with a lung-specific promoter were hemorrhaged by removing 30% of blood volume. After hemorrhage, the lung wet to dry weight ratios increased from 5.4 +/- 0.11 in unmanipulated control mice to 6.3 +/- 0.16 in wild-type mice, but to only 5.60 +/- 0.17 in the EC-SOD transgenic mice (p < 0.05 compared with hemorrhaged wild-type). Hemorrhage-induced lipid peroxidation, as assessed by lung F(2) isoprostanes, was lower in the EC-SOD transgenic mice (3.4 +/- 0.3 microg/lung) compared with wild-type mice (1.9 +/- 0.2 microg/lung; p < 0.05). Compared with wild-type, EC-SOD transgenic mice had attenuated the hemorrhage-induced increase in both pulmonary nuclear factor kappa B (NK-kappaB) activation (relative absorbance 1.1 +/- 0.2 for EC-SOD transgenic versus 2.5 +/- 0.1 for wild-type; p < 0.05) and myeloperoxidase activity (5.1 +/- 0.87 units/g for EC-SOD transgenic versus 11.3 +/- 1.8 units/g for wild-type; p < 0.01). Thus, overexpression of pulmonary EC-SOD in the mouse lung attenuates lung injury after hemorrhage.

Antiinflammatory Effects of Hydrogen Peroxide in Neutrophil Activation and Acute Lung Injury

“…The present results, showing that inactivation or absence of catalase is antiinflammatory in neutrophils and reduces the severity of ALI, support this hypothesis. Similarly, the efficacy of EC-SOD and EC-SOD mimetics, which facilitate the transition of superoxide to H 2 O 2 , in reducing the severity of ALI in experimental models (69,70), also is consistent with benefit being associated with antioxidant approaches that specifically result in increases in intracellular H 2 O 2 concentrations. …”

The R213G polymorphism in SOD3 protects against allergic airway inflammation

“…(42)(43)(44)(45)(46)(47). Allergic asthma, oxidative stress, and lung inflammation go hand-in-hand (48,49).…”

Decreased pulmonary extracellular superoxide dismutase during systemic inflammation

“…Thus, it is highly possible that overexpressed EC-SOD from tissues other than lungs may have protected lungs from oxidative damage. To examine such possibility, transgenic mice with lung-specific overexpression of EC-SOD would be useful [20]. Taken together, it would be reasonable to conclude that the inflammation-mediated loss of EC-SOD is causally associated with the pulmonary oxidative damage and mortality during endotoxemia.…”

“…Several studies, using either EC-SOD-null mice or transgenic mice overexpressing EC-SOD, have shown that this enzyme plays important roles in protecting lung tissues from certain types of physiological stress such as hyperoxia [17,18] and hemorrhage [19,20]. However, a role of EC-SOD in lungs during SIRS has not been clearly defined.…”