Cigarette smoke and Pseudomonas aeruginosa synergistically cause ARDS via impairment of mitophagic flux and NLRP3 inflammasome activation

Abstract

Itis increasingly recognized that cigarette smoke (CS) increases the incidenceand mortality associated with acute respiratory distress syndrome (ARDS), however, the underlying mechanism(s) for this is unknown. Pseudomonas aeruginosa is a frequent pathogen causing pneumonia, which is the most prevalent cause of ARDS. Whether CS increases prevalence of ARDS in individuals with P. aeruginosa infection is unknown. We have previously shown that CS increases severity of acute lung injury in mice challenged by lipopolysaccharide. In this study, we demonstrated that exposure of mice to CS either briefly (6h) or sub‐acutely (2weeks) suppressed lung bacterial clearance and exacerbated P. aeruginosa (PA103)‐induced lung edema, inflammation and mortality. CS and PA103 also synergistically increased lung microvascular endothelial cell permeability in vitro. To investigate the mechanisms of CS priming for lung injury, we used the clinically relevant double‐hit mouse model of ARDS induced by CS priming, followed by PA103 infection. We found that CS increased mitochondrial fission and mitochondrial oxidativestress and inhibition of mitochondrial fission and oxidative stress prevented CS‐induced increase in endothelial permeability. CS pre‐exposure did not affect PA103‐induced increase in steady‐state mitophagy, but impaired mitophagic fluxin alveolar macrophages and lung endothelial cells; an effect associated with accumulation of fragmented/swollen mitochondria and double‐membraned mitophagosomes in the lungs and NLRP3 inflammasome activation in alveolar macrophages. We further found that inhibition of NLRP3 inflammasome signaling attenuated CS/PA103 double‐hit‐induced lung inflammation and lung edema and improved bacterial clearance, as well as overall animal survival. Our results suggest that CS/PA103 double‐hit injury causes ARDS via enhancement of mitochondrial fission and impairment of mitophagic flux and resultant NLRP3 inflammasome activation. Suppression of mitochondrial fission, improvement of mitophagic flux and inhibition of the inflammasome may be novel targeted therapeutic strategies for smokers with ARDS.Support or Funding InformationCOBREP20GM103652 (Rounds, Lu), R01 HL130230 (Lu), VA Merit Review (Rounds)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.