The lung is highly susceptible to oxidative stress because of its exposure to high oxygen tension and environmental stressors, making tight regulation of the redox environment essential for homeostasis and disease pathogenesis. Extracellular superoxide dismutase (EC-SOD, sod3) is an important antioxidant enzyme in the lung that catalyzes the dismutation of superoxide into hydrogen peroxide and oxygen, thereby regulating the redox environment of the extracellular matrix, cell surfaces, and lining fluids of the lung. This review summarizes the structural features, post-translational regulation, genetic variations, and cellular sources of EC-SOD, with a particular focus on its role in acute respiratory distress syndrome (ARDS). We highlight evidence demonstrating that loss of EC-SOD exacerbates dysregulated immune responses, whereas enhanced EC-SOD activity confers protection in multiple experimental models of acute lung injury. We also discuss how inflammatory signaling, epigenetic regulation, aging, and genetic polymorphisms in the sod3 gene influence EC-SOD expression and function. Finally, we review emerging therapeutic strategies, including SOD mimetics and mRNA-based approaches, and address the challenges associated with non-specific antioxidant therapies in ARDS. Collectively, the data position EC-SOD as a central regulator of extracellular redox signaling and a promising, mechanism-driven therapeutic target in acute lung injury and ARDS.
Osier et al. (Fri,) studied this question.