Silver nanoparticle-activated COX2/PGE2 axis involves alteration of lung cellular senescence in vitro and in vivo.

Abstract Silver nanoparticles (AgNPs) are widely used as antimicrobial agents and resulted in their accumulation in environment. The purpose of this study was to investigate the detailed molecular mechanisms underlying AgNP-induced lung cellular senescence which has been proposed as a pathogenic driver of chronic lung disease. Herein, we demonstrate that exposure to AgNPs elevates multiple senescence biomarkers in lung cells, with cell cycle arrest in the G2/M phase, and potently activates genes of the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cell line MRC5. Fluorescence-based assay also reveals that apoptosis induced by AgNPs is associated with senescence. Furthermore, we show that AgNPs cause premature senescence through an increase in transcription factor nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX2) expression and over-production of prostaglandin E2 (PGE2) in lung cells. Inhibition of COX2 reduces AgNPs-induced senescence to a normal level. Moreover, AgNPs also induce upregulation of COX2 and accelerate lung cellular senescence in vivo and cause mild fibrosis in the lung tissue of mice. Taken together, our studies support a critical role of AgNPs in the induction of lung cellular senescence via the upregulation of the COX2/PGE2 intracrine pathway, and suggest the adverse effects to the human respiratory system.