Regulation of extracellular superoxide dismutase

Extracellular superoxide dismutase (EC-SOD) is the primary mammalian superoxide dismutase in the extracellular space and is abundant in the lung. Previous investigators have found that EC-SOD protects the lung during hyperoxia, suggesting that extracellular reactive oxygen species play an important role in lung injury mediated by oxidative stress. Using transgenic mice that target lung specific overexpression human EC-SOD, we found that EC-SOD protected the lung from injury during hemorrhage and bleomycin-induced fibrosis. The level EC-SOD expression also inversely correlated with the recruitment of activated neutrophils to the lung after hemorrhage. Thus, EC-SOD may attenuate lung injury via two mechanisms. First, by reducing the level of superoxide in the alveolar interstitium, there would be less direct superoxide-mediated injury to proteins, lipids, and DNA. Second, EC-SOD could diminish superoxide-mediated recruitment of inflammatory cells to the injured lung, thereby indirectly reducing the lung injury that follows recruitment of activated neutrophils to the lung.; The molecular structure of EC-SOD may be an important determinant in how EC-SOD protects the extracellular space. A unique feature of EC-SOD is a span of six consecutive, positively charged amino acids in the carboxyterminus. These residues are essential for EC-SOD's binding to heparin and the extracellular matrix (ECM). This report characterizes post-translational proteolytic processing of the carboxyterminus and identifies furin as the processing protease. Another feature that may mediate EC-SOD's affinity for the extracellular space is homopolymerization. We describe the existence of high molecular weight polymers and postulate that their high molecular weight and multiple heparin-binding domains may decrease the mobility of EC-SOD within the extracellular space, thereby localizing EC-SOD activity to the site of secretion.