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.

Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury

“…Notably, we detected evidence of this relationship in injured dog lungs, as IL-1β, TNF-α and IL-8 levels were all significantly lower in APT102-treated dogs. In particular our observation of blunted IL-1β production is in accordance with previous reports that show eATP engagement of the P2X 7 receptor promotes NLRP3 inflammasome activation 12, 13 . IL-1β production in this manner is also critically dependent on P2X 7 receptor-mediated oligomerization of non-selective cation channels leading to a large outward K + current 29 .…”

“…This in turn leads to eATP engagement of P2 family purigenic receptor family members that promote inflammatory mediator expression 11 . For example, eATP stimulation of the P2X 7 receptor triggers Nod-like receptor, pyrin domain containing 3 (NLRP3) inflammasome activation leading to IL-1β post-translational modification and release 12–14 .…”

NLRP3 Inflammasome Activation Is Essential for Paraquat-Induced Acute Lung Injury

“…The NLRP3 inflammasome was required for the development of acute lung injury caused by LPS/mechanical ventilation [33], hyperoxia [34], hemorrhagic shock [35], etc. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels; attenuated the recruitment of inflammatory cells and elevation of IL-1β, TNF-α, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1; suppressed NF-κB levels; and exerted a protective effect against acute lung injury [34].…”

Acute exacerbation of rheumatoid interstitial lung disease during the maintenance therapy with certolizumab pegol

“…Emerging genetic and pharmacological evidence suggests that persistent NLRP3 activation by irritants may cause the progression of several chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), COPD, and asthma [15]. Recent studies suggest a novel role for IL-1β and the NLRP3 inflammasome in hypoxia associated with ALI [16]. The increase in circulating cleaved IL-Iβ levels during the period of acute exacerbation of RA-ILD in the present case suggests a mechanism involving enhanced NLRP3 inflammasome activation.…”