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Oxidative stress and inflammation play a crucial role in the pathogenesis of ARDS. Extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is an important enzymatic defense against superoxide. Human single-nucleotide polymorphism in matrix binding region of EC-SOD leads to the substitution of arginine to glycine at position 213 (R213G) and results in release of EC-SOD into alveolar fluid, without affecting enzyme activity. We hypothesized that R213G EC-SOD variant protects against lung injury and inflammation via the blockade of neutrophil recruitment in infectious model of methicillin-resistant S. aureus (MRSA) pneumonia. After inoculation with MRSA, wild-type (WT) mice had impaired integrity of alveolar-capillary barrier and increased levels of IL-1\u03b2, IL-6, and TNF-\u03b1 in the broncho-alveolar lavage fluid (BALF), while infected mice expressing R213G EC-SOD variant maintained the integrity of alveolar-capillary interface and had attenuated levels of proinflammatory cytokines. MRSA-infected mice expressing R213G EC-SOD variant also had attenuated neutrophil numbers in BALF and decreased expression of neutrophil chemoattractant CXCL1 by the alveolar epithelial ATII cells, compared with the infected WT group. The decreased neutrophil numbers in R213G mice were not due to increased rate of apoptosis. Mice expressing R213G variant had a differential effect on neutrophil functionality\u2014the generation of neutrophil extracellular traps (NETs) but not myeloperoxidase (MPO) levels were attenuated in comparison with WT controls. Despite having the same bacterial load in the lung as WT controls, mice expressing R213G EC-SOD variant were protected from extrapulmonary dissemination of bacteria. <\/jats:p>","DOI":"10.1152\/ajplung.00217.2022","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T16:18:35Z","timestamp":1675786715000},"page":"L445-L455","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Release of extracellular superoxide dismutase into alveolar fluid protects against acute lung injury and inflammation in <i>Staphylococcus aureus<\/i> pneumonia"],"prefix":"10.1152","volume":"324","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7304-881X","authenticated-orcid":false,"given":"Christina","family":"Sul","sequence":"first","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Anschutz Medical 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