The Mechanism Of Silica Nanoparticles Triggering Lung Inflammation Through ROS/PARP-1/TRPM2 Signaling Pathway In Mice

Silica nanoparticles(SiNPs),as one of the most important nano-materials,have been widely used in various industries in daily life,such as cosmetics,food additives,pharmaceuticals,paints,etc.With the risk of exposure increasing,the safety of SiNPs has also received increasing attention.As the main exposure approach,SiNPs can cause severe lung inflammation after exposure to the respiratory tract.Although mechanisms such as ROS,apoptosis,autophagy,and lysosomal damage have been studied,the specific molecular mechanisms are not clear,and the correlation among these factors also lacks strong evidences.This study aims to further explore the specific mechanism of lung inflammation induced by SiNPs in order to provide new prevention and treatment strategies for pulmonary inflammation caused by related particulate matter exposure.In this study,C57BL/6 wild-type mice were exposed with SiNPs by bronchial instillation(it)to construct an animal model of lung inflammation.Increase of cytokines and total protein release,lactate dehydrogenase(LDH)production and inflammatory cell infiltration confirmed further that SiNPs caused inflammation in the lungs of mice.For further mechanistic studies,we used non-tumorigenic human bronchial epithelial cells(Ad12-SV40 immortalized)BEAS-2B to test the toxicity of SiNPs in vitro.We found that after SiNPs exposure,the cell viability decreased significantly in a time-and concentration-dependent way,and inflammation also increased significantly.The results are consistent with observations in vivo.Subsequent research found that SiNPs could cause a significant increase in intracellular reactive oxygen species(ROS)production,which in turn activated poly(ADP-ribose)polymerase-1(PARP-1)to release the adenosine diphosphate ribose(ADPR),a endogenous agonist of transient receptor potential melastatin 2(TRPM2).Thus,activating TRPM2 channel blocked the normal autophagy process and triggered inflammatory responses by disrupting lysosomal function,including lysosomal alkalization and lysosomal membrane permeability(LMP)change.Finally,we found that lung inflammation and injury in Trpm2-/-mice were significantly mitigated compared with wild-type mice.In summary,our work suggested that SiNPs triggered lung inflammation via ROS / PARP-1/ TRPM2 signaling pathway,which provided a new perspective for explaining SiNPs-mediated lung injury,more importantly,provided a novel target for the prevention and treatment of inflammatory diseases caused by nanomaterials.