Chemical injury history increases pulmonary susceptibility to PM2.5 inhalation: Toxicological evidence for risk assessment in a neglected vulnerable population.

Environmental health risk assessments typically prioritize vulnerable populations such as the elderly, children, and individuals with respiratory diseases. However, individuals with a history of chemical-induced lung injury are rarely considered, despite potentially heightened sensitivity to air pollutants. Therefore, this study investigated the pulmonary health risks of particulate matter (PM) 2.5 exposure in a chemical lung injury model, reflecting realistic exposure conditions. Mice were intratracheally administered polyhexamethylene guanidine phosphate (PHMG-P; 0.3 mg/kg), followed by nose-only exposure to PM2.5 (8.88 ± 1.77 mg/m3, 6 h/day for 2 weeks) to establish the model. PHMG-P resulted in broncho-alveolar and mucous cell hyperplasia and granulomatous inflammation, with increased inflammatory cells and proteins in lungs. Subsequent PM2.5 exposure significantly exacerbated fibrotic lesions and broncho-alveolar hyperplasia, with enhanced inflammatory proteins including interleukin (IL)-4, IL-6, IL-13, monocyte chemoattractant protein-1, and CXC-chemokine Ligand 1. Transcriptomic analysis revealed macrophage alternative activation, IL-4/IL-13 signaling pathways, and upstream regulators EGR1 and IGF1-mediated exacerbation of pulmonary inflammation and fibrosis. These findings indicate that pre-existing chemical lung injury increases vulnerability to PM2.5, thereby highlighting the importance of including prior chemical exposure history in defining susceptible populations.