Anti-oxidant treatment after injury suppresses second hit immune priming

Background Pulmonary contusion is a common injury that often results in priming for exaggerated inflammatory responses to a second hit. Previous studies used a mouse model of pulmonary contusion and showed an early and sustained reduction of SIRT1 protein and activity in the lung and BAL cells of injured mice. Sustained decrease in SIRT1 was associated with a primed phenotype in injured mice challenged with an inflammatory stimulus. This study tests the hypothesis that pulmonary contusion induces oxidant production that modifies and decreases SIRT1 and primes the lung for the second hit response. Methods A mouse model of pulmonary contusion was used to investigate injury induced oxidant changes in SIRT1. Second hit responses were evaluated by infection (S. pneumoniae) and inflammatory challenge using bacterial lipopolysaccharide. BAL, lung tissue and blood were collected and used to evaluate inflammatory responses and SIRT1 levels, oxidant modification, and activity. Levels of NO in the BAL from mice and patients with PC were also assessed. Results We found that oxidants produced as a result of pulmonary contusion resulted in modification of SIRT1. S-Nitrosylation was observed and correlated with increased inducible nitric oxide synthase expression after injury. Anti-oxidant treatment of injured mice preserved SIRT1 activity, decreased second hit responses and improved lung function. Elevated NO levels in the BAL of PC patients was associated with ARDS or diagnosis of pneumonia. Conclusions We conclude that oxidative stress in the lung after injury induces redox modification of SIRT1 and contributes to priming of the lung for a second hit response. Anti-oxidant treatment suggests that SIRT1 activity after injury may be beneficial in suppressing second hit responses. This work was supported, in part, by the Clowes/ACS/AAST Award and GM083154 (JH), R33CA1777461 and R21ES025645 (CMF), and AI065791 and AI079144 (CM, BY). All authors declare no conflicts of interest. Corresponding author: J. Jason Hoth, MD., PhD., Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. e-mail: jhoth@wakehealth.edu © 2018 Lippincott Williams & Wilkins, Inc.

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