NLRP3 inflammasome activation determines the fibrogenic potential of PM 2.5 air pollution particles in the lung. - GreenMedInfo Summary

Airborne fine particulate matter (PM) is known to cause respiratory inflammation such as chronic obstructive pulmonary disease and lung fibrosis. NLRP3 inflammasome activation has been implicated in these diseases; however, due to the complexity in PMcompositions, it is difficult to differentiate the roles of the components in triggering this pathway. We collected eight real-life PMsamples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis. In vitro assays showed that although the PMparticles did not induce significant cytotoxicity at the dose range of 12.5 to 100 µg/mL, they induced potent TNF-α and IL-1β production in PMA differentiated THP-1 human macrophages and TGF-β1 production in BEAS-2B human bronchial epithelial cells. At the dose of 100 µg/mL, PMinduced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release, leading to IL-1β production. This was confirmed by using NLRP3- and ASC-deficient cells as well as a cathepsin B inhibitor, ca-074 ME. Administration of PMvia oropharyngeal aspiration at 2 mg/kg induced significant TGF-β1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21 days post-exposure, suggesting PMhas the potential to induce pulmonary fibrosis. The ranking of in vitro IL-1β production correlates well with the in vivo total cell count, TGF-β1 production, and collagen deposition. In summary, we demonstrate that the PMis capable of inducing NLRP3 inflammasome activation, which triggers a series of cellular responses in the lung to induce fibrosis.