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Inflammation and Injury Mechanical Stretch-Induced Lung Alveolar Macrophages Contributes to Activation of NLRP3 Inflammasome in

Mechanical ventilation of lungs is capable of activating the innate immune system and inducing sterile inﬂammatory response. The proinﬂammatory cytokine IL-1 b is among the deﬁnitive markers for accurately identifying ventilator-induced lung inﬂammation. However, mechanisms of IL-1 b release during mechanical ventilation are unknown. In this study, we show that cyclic stretch activates the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inﬂammasomes and induces the release of IL-1 b in mouse alveolar macrophages via caspase-1– and TLR4-dependent mechanisms. We also observed that NADPH oxidase subunit gp91 phox was dispensable for stretch-induced cytokine production, whereas mitochondrial generation of reactive oxygen species was required for stretch-induced NLRP3 inﬂammasome activation and IL-1 b release. Further, mechanical ventilation activated the NLRP3 inﬂammasomes in mouse alveolar macrophages and increased the production of IL-1 b in vivo. IL-1 b neutralization signiﬁcantly reduced mechanical ventilation-induced inﬂammatory lung injury. These ﬁndings suggest that the alveolar macrophage NLRP3 inﬂammasome may sense lung alveolar stretch to induce the release of IL-1 b and hence may contribute to the mechanism of lung inﬂammatory injury during mechanical ventilation. The Journal of Immunology , 2013, 190: 3590–3599.