title: The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury.
abstract: IL-1β is a potent proinflammatory cytokine that is implicated in the pathogenesis of acute respiratory distress syndrome. We hypothesized that LPS and mechanical ventilation (MV) together could lead to IL-1β secretion and the development of acute lung injury (ALI), and that this process would be dependent on caspase-1 and the nucleotide binding domain and leucine-rich repeat (NLR) pyrin domain containing 3 (NLRP3) inflammasome activation. The objectives of this study were to determine the specific role of IL-1β, caspase-1, and the NLRP3 inflammasome in a two-hit model of ALI due to LPS plus MV. We used a two-hit murine model of ALI in which both inhaled LPS and MV were required for the development of hypoxemia, pulmonary neutrophil infiltration, and alveolar leakage. Nlrp3-deficent and Casp1-deficient mice had significantly diminished IL-1β levels in bronchoalveolar lavage fluid, and were specifically protected from hypoxemia, despite similar alveolar neutrophil infiltration and leakage. The IL-1 receptor antagonist, Anakinra, significantly improved the specific development of hypoxemia without significant effects on neutrophil infiltration or alveolar leakage. MV resulted in increased bronchoalveolar lavage extracellular ATP and alveolar macrophage apoptosis as triggers of NLRP3 inflammasome activation. NLRP3 inflammasome activation and IL-1β production play a key role in ALI caused by the combination of LPS and MV, particularly in the hypoxemia associated with acute respiratory distress syndrome. Blocking IL-1 signaling in this model specifically ameliorates hypoxemia, without affecting neutrophil infiltration and alveolar leakage, disassociating these readouts of ALI. MV causes alveolar macrophage apoptosis, a key step in the activation of NLRP3 inflammasome and production of IL-1β.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Jones
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Crother
authors.forename: Romer A
authors.initials: RA
authors.lastname: Gonzalez-Villalobos
authors.forename: Madhulika
authors.initials: M
authors.lastname: Jupelli
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D000860:Hypoxia / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects / Q000379:methods; D015398:Signal Transduction / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D007375:Interleukin-1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; D020170:Caspase 1