Abstract
Acute respiratory distress syndrome is a serious illness accounting for 10% of ICU admissions and has a high mortality of 31-45%, with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of acute respiratory distress syndrome. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme EC-SOD (extracellular superoxide dismutase) are protected against Staphylococcus aureus pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue-binding affinity and elevated alveolar and plasma EC-SOD amounts, although the redox-regulated mechanisms responsible for protection against S. aureus are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against S. aureus pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared with wild-type mice with S. aureus pneumonia, platelet activation, formation of platelet-neutrophil aggregates, and influx of neutrophils and platelet-neutrophil aggregates into the lung are decreased in the infected R213G mice. Furthermore, pretreatment with a MnTE-2-PyP SOD mimetic protects against S. aureus-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of S. aureus-induced acute lung injury.