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ilica nanoparticles (SiO2NPs) cause oxidative stress in respiratory system.Meanwhile, human cells launch adaptive responses to overcome SiO2NP toxicity.However,besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown.In this study, we demonstrated that SiO2 NP induced the expression of fcllistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human epithelial cells (A549).The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment.The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region.Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue.Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS).Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems.