NLRP3 inflammasome activation in cigarette smoke priming for Pseudomonas aeruginosa-induced acute lung injury
Alexis White,
Zhengke Wang,
Xing Wang,
Michelle King,
Cynthia Guo,
Chris Mantsounga,
Alfred Ayala,
Alan R. Morrison,
Gaurav Choudhary,
Frank Sellke,
Eboni Chambers,
Lorraine B. Ware,
Sharon Rounds,
Qing Lu
Affiliations
Alexis White
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Zhengke Wang
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Xing Wang
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Michelle King
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Cynthia Guo
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Chris Mantsounga
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Alfred Ayala
Department of Surgery, The Warren Alpert Medical School of Brown University and Lifespan-Rhode Island Hospital, Providence, RI, USA
Alan R. Morrison
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Gaurav Choudhary
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Frank Sellke
Cardiothoracic Surgery, The Warren Alpert Medical School of Brown University and Lifespan-Rhode Island Hospital, Providence, RI, USA
Eboni Chambers
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
Lorraine B. Ware
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
Sharon Rounds
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Qing Lu
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA; Corresponding author.National Heart, Lung, and Blood Institute, NIH, USA.
It is increasingly recognized that cigarette smoke (CS) exposure increases the incidence and severity of acute respiratory distress syndrome (ARDS) in critical ill humans and animals. However, the mechanism(s) is not well understood. This study aims to investigate mechanism underlying the priming effect of CS on Pseudomonas aeruginosa-triggered acute lung injury, by using pre-clinic animal models and genetically modified mice. We demonstrated that CS impaired P. aeruginosa-induced mitophagy flux, promoted p62 accumulation, and exacerbated P. aeruginosa-triggered mitochondrial damage and NLRP3 inflammasome activation in alveolar macrophages; an effect associated with increased acute lung injury and mortality. Pharmacological inhibition of caspase-1, a component of inflammasome, attenuated CS primed P. aeruginosa-triggered acute lung injury and improved animal survival. Global or myeloid-specific knockout of IL-1β, a downstream component of inflammasome activation, also attenuated CS primed P. aeruginosa-triggered acute lung injury. Our results suggest that NLRP3 inflammasome activation is an important mechanism for CS primed P. aeruginosa-triggered acute lung injury. (total words: 155).
