Hyperglycemia modulates lung epithelial susceptibility to PM_2.5-induced DNA damage, autophagy, and...

Hyperglycemia is a metabolic stressor that may modulate the pulmonary response to airborne pollutants. This study investigated the effects of fine particulate matter (PM_2.5) on lung epithelial cells and the lung transcriptome under normoglycemia and hyperglycemic conditions. A549 cells were cultured in normal (5.5 mM) or high (20 mM, 30 mM) glucose media followed by exposure to increasing doses of PM₂.₅ (0-100 μg/mL). Cells cultured with high glucose media reduced cell viability and increased basal autophagy, while PM₂.₅ induced dose-dependent apoptosis, DNA damage, autophagy activation, and EMT. High glucose culture reduced basal ROS generation, which was increased by treatment of PM_2.5. Pretreatment of the ROS scavenger N-acetyl-l-cysteine reversed the expression of apoptotic (Bax), DNA damage (phosphor-γ-H2AX), autophagic (LC3 and p62), and mesenchymal (vimentin) markers under all glucose conditions. Furthermore, inhibition of autophagic flux using chloroquine further increase Bax expression, while reversing EMT (E-Cadherin and SNAIL) and DNA damage markers expressions across all tested glucose concentrations. Transcriptomic analysis of hyperglycemic mice exposed to PM₂.₅ revealed differential enrichment of pathways related to oxidative phosphorylation, DNA repair, and immune signaling, indicating additive or synergistic effects depending on hyperglycemia severity. Together, these findings demonstrated that hyperglycemia selectively reshapes multiple aspects of PM₂.₅-induced cellular stress, leading to autophagy dysregulation, attenuated EMT, and significantly exacerbates DNA damage susceptibility. This study provides mechanistic insight into how metabolic disorders increase vulnerability to environmental pollutants.