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Acute lung injury (ALI) caused by acid aspiration often accompanies bacterial components leading to exaggerated inflammation and can result in acute respiratory distress syndrome (ARDS), but the underlying mechanisms behind such an exacerbation remain unclear. NLRP3 inflammasome and mitochondrial ROS (mtROS) have been implicated in ALI but its role in injury caused through two hit i.e. Hydrochloric acid (HCl) + Lipopolysaccharide (LPS) is not known. Therefore, the present study is designed to elucidate the role of mtROS-NLPR3 inflammasome upon “two-hit” mediated ALI. Our data showed that “two-hit” induced ALI results in aggravated lung inflammation as compared to either of single hit(s) as reflected by a steep increase in inflammatory cells particularly neutrophils in bronchoalveolar lavage fluid (BALF). Further, enhanced inflammation was associated with increased mtROS as depicted by data on mean fluorescence intensity (MFI) of MitoSOX +  neutrophils and macrophages in BALF of two-hit simulated mice. Importantly, ALI results in activation of NLRP3 inflammasome as reflected by active caspase-1 protein expression and IL-1β levels. Interestingly, NLRP3 inflammasome inhibitor, MCC950 suppressed the lung inflammation remarkably. Further, Mito-tempo, a mitochondrial-targeted antioxidant, halted “two-hit” mediated NLRP3 inflammasome activation and IL-1β release followed by amelioration of lung inflammation. Suppression in MFI of MitoSOX +  stained neutrophils and macrophages by Mito-tempo was associated with down-regulation of phospho-p65-NF-κB and its dependent genes (IL-1β/TNF-α/IL-6). Overall, our data suggest that NLRP3 inflammasome activation by mtROS plays a critical role in pathogenesis of exaggerated inflammation and therefore targeting mtROS-NLRP3 inflammasome axis may be an attractive option for combating ALI/ARDS.

Implication of mitochondrial ROS-NLRP3 inflammasome axis during two-hit mediated acute lung injury in mice