Activation of NLRP3 inflammasome in alveolar macrophages mediates mechanical stretch‐induced lung inflammation

Mechanical ventilation is capable of activating the innate immune system and inducing sterile inflammatory response. The proinflammatory cytokine IL‐1β is among the definitive markers for accurately identifying ventilator‐induced lung inflammation. However, mechanisms of IL‐1β release from inflammatory cells during mechanical ventilation are unknown. Here we show that cyclic stretch activates the NLRP3 inflammasomes and induces release of IL‐1β and IL‐18 in mouse alveolar macrophages via caspase‐1‐ and TLR4‐dependent mechanisms. We also observed that gp91phox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit is dispensable for stretch‐induced cytokine production whereas mitochondrial generation of reactive oxygen species (ROS) was required for stretch‐induced NLRP3 inflammasome activation and IL‐1β release. Furthermore, mechanical ventilation with a high tidal volume activates NLRP3 inflammasome in mouse alveolar macrophages and increases the production of IL‐1β and IL‐18 in vivo. These findings suggest that alveolar macrophage‐associated NLRP3 inflammasome has an airway stretch‐sensing capacity that induces the release of IL‐1β, and hence may contribute to the mechanism of lung inflammatory injury.