Airborne fine particulate matter(PM_(2.5))is known to cause respiratory inflammation such as chronic obstructive pulmonary disease and lung fibrosis.NLRP3 inflammasome activation has been implicated in these diseases;...Airborne fine particulate matter(PM_(2.5))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 PM_(2.5)compositions,it is difficult to differentiate the roles of the components in triggering this pathway.We collected eight real-life PM_(2.5)samples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis.In vitro assays showed that although the PM_(2.5)particles did not induce significant cytotoxicity at the dose range of 12.5to 100μg/m L,they induced potent TNF-αand IL-1βproduction in PMA differentiated THP-1 human macrophages and TGF-β1 production in BEAS-2B human bronchial epithelial cells.At the dose of 100μg/m L,PM_(2.5)induced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release,leading to IL-1βproduction.This was confirmed by using NLRP3-and ASC-deficient cells as well as a cathepsin B inhibitor,ca-074 ME.Administration of PM_(2.5)via oropharyngeal aspiration at 2 mg/kg induced significant TGF-β1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21days post-exposure,suggesting PM_(2.5)has the potential to induce pulmonary fibrosis.The ranking of in vitro IL-1βproduction correlates well with the in vivo total cell count,TGF-β1 production,and collagen deposition.In summary,we demonstrate that the PM_(2.5)is capable of inducing NLRP3 inflammasome activation,which triggers a series of cellular responses in the lung to induce fibrosis.展开更多
基金supported by the National Natural Science Foundation of China(No.31570899)the Joint construction project of Henan Province Medical Science and Technology Research Plan(No.SB201903032)。
文摘Airborne fine particulate matter(PM_(2.5))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 PM_(2.5)compositions,it is difficult to differentiate the roles of the components in triggering this pathway.We collected eight real-life PM_(2.5)samples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis.In vitro assays showed that although the PM_(2.5)particles did not induce significant cytotoxicity at the dose range of 12.5to 100μg/m L,they induced potent TNF-αand IL-1βproduction in PMA differentiated THP-1 human macrophages and TGF-β1 production in BEAS-2B human bronchial epithelial cells.At the dose of 100μg/m L,PM_(2.5)induced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release,leading to IL-1βproduction.This was confirmed by using NLRP3-and ASC-deficient cells as well as a cathepsin B inhibitor,ca-074 ME.Administration of PM_(2.5)via oropharyngeal aspiration at 2 mg/kg induced significant TGF-β1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21days post-exposure,suggesting PM_(2.5)has the potential to induce pulmonary fibrosis.The ranking of in vitro IL-1βproduction correlates well with the in vivo total cell count,TGF-β1 production,and collagen deposition.In summary,we demonstrate that the PM_(2.5)is capable of inducing NLRP3 inflammasome activation,which triggers a series of cellular responses in the lung to induce fibrosis.
