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-1b is among the definitive markers for accurately identifying ventilator-induced lung inflammation. However, mechanisms of IL-1b 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-1b 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-1b release. Further, mechanical ventilation activated the NLRP3 inflammasomes in mouse alveolar macrophages and increased the production of IL-1b in vivo. IL-1b 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-1b and hence may contribute to the mechanism of lung inflammatory injury during mechanical ventilation. M echanical ventilation is necessary to support patients with acute lung injury (ALI) or its most severe form, acute respiratory distress syndrome (ARDS); however, it has also been shown to exacerbate lung injury, the so-called ventilator-induced lung injury (VILI) (1). VILI is characterized by inflammation associated with robust release of proinflammatory cytokines and activation of inflammatory signaling pathways (1). A variety of inflammatory mediators are released into the distal air spaces during ALI (2), and among these is IL-1b, a potent proinflammatory cytokine initiating and amplifying lung inflammation in patients (3). IL-1b can stimulate the production of a variety of chemokines (e.g., IL-8, MCP-1, and MIP-1a) (4). A recent study indicates that IL-1b is critical for the pathogenesis of VILI (5). Activation of the inflammatory response, including increased IL-1 signaling, is a major mechanism of alveolar barrier dysfunction in VILI (5). Studies in patients have demonstrated that IL-1b is among the best markers of ventilator-induced lung inflammation (6). Findings also suggest that IL-1 is a key regulator of inflammation. IL-1b receptor antagonist and anti–IL-1b Ab have been demonstrated to prevent ALI (2, 5, 7). Alveolar macrophages (AMs) residing in the alveolar space account for 5% of peripheral lung cells (8). Under physiological condition, leukocyte population in the alveolar space is dominated by AMs (comprising .90% of the total cells), with the remainder being mainly dendritic cells and T cells. …