Release of extracellular superoxide dismutase into alveolar fluid protects against acute lung injury and inflammation in Staphylococcus aureus pneumonia

Abstract

Acute respiratory distress syndrome (ARDS) remains a significant cause of morbidity and mortality in critically ill patients. Oxidative stress and inflammation play crucial role in pathogenesis of ARDS. Extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is important enzymatic defense against superoxide. Human single nucleotide polymorphism in matrix binding region of EC-SOD leads to 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 blockade of neutrophil-recruitment in infectious model of methicillin-resistant S. aureus (MRSA) pneumonia. After inoculation with MRSA, WT mice had impaired integrity of alveolar-capillary barrier and increased levels of IL-1β, IL-6, and TNF-α 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 to the infected WT group. The decreased neutrophil numbers in R213G mice were not due to increased rate of apoptosis. Mice expressing R213G variant had differential effect on neutrophil functionality, - the generation of neutrophil extracellular traps (NETs) but not myeloperoxidase (MPO) levels were attenuated in comparison to 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.

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“…As an anti-oxidative stress substance, SOD plays an important role in protecting the lung. In addition to having anti-oxidative effect within cells, extracellular superoxide dismutase in alveolar fluid is protective for methicillin-resistant Staphylococcus aureus inoculation-triggered inflammation and acute lung injury ( Sul et al, 2023 ).…”

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“…While both male and female mice were utilized in this study, we did not perform analyses of any potential sex dimorphisms. MRSA pneumonia is not a natural pathogen in mice and is generally rapidly cleared by the host in murine models [ 35 ]. For this reason, an early timepoint was chosen for treatment and subsequent sample processing to capture the inflammatory response induced by this infectious model.…”