Integrated toxicological analysis links air pollution-associated acute respiratory distress syndrome signatures to benzo[a]pyrene-induced acute lung injury.

Acute respiratory distress syndrome (ARDS) is associated with high mortality, and increasing evidence suggests that air pollution may contribute to its development. However, the molecular mechanisms linking pollutant exposure to severe inflammatory lung injury remain incompletely understood. In this study, we integrated local clinical association data, bioinformatic analyses, molecular interaction prediction, and in vivo toxicological validation to investigate potential mechanisms underlying pollution-associated respiratory injury. Monthly hospital admissions for ARDS were positively associated with ambient particulate matter concentrations (PM2.5 and PM10) in Yangzhou, China. Analysis of the GSE76293 dataset identified 167 overlapping genes between pollutant-related targets and ARDS-associated differentially expressed genes, which were mainly enriched in inflammatory and immune-response pathways. Machine learning prioritized three candidate targets, NLRC4, ETS2, and VNN1. Because polycyclic aromatic hydrocarbons (PAHs) are representative toxic components of particulate matter, benzo[a]pyrene (BaP) was selected for in vivo validation. Molecular docking and molecular dynamics analyses supported stable interactions between PAH-related compounds and the candidate proteins. In mice, BaP exposure induced acute lung injury, as indicated by histopathological damage, increased lung wet-to-dry weight ratio, and elevated inflammatory mediators in bronchoalveolar lavage fluid. BaP exposure was also accompanied by increased expression of NLRC4/GSDMD-related signaling, together with upregulation of ETS2 and VNN1 in lung tissue. These findings support a potential mechanistic link between particulate pollution-related toxicants and acute inflammatory lung injury relevant to ARDS.