Modulatory effects of CeO2 nanoparticles on bleomycin-induced active pulmonary disease processes in animal and human airway epithelium models

Abstract Background Understanding the impacts of inhaled insoluble nanomaterials as they are encountered in the environment and workplace, in injured lungs remains limited, particularly with respect to their role in the progression or mitigation of lung pathology. While some studies suggest potential protective effects of cerium(IV) oxide nanoparticles (CeO₂NPs) under certain conditions, their influence during active disease processes is unclear. This study builds on prior work to investigate the effects of CeO₂NP aerosols on bleomycin-induced pulmonary injury and active disease processes. Method To establish conditions of active pulmonary disease processes, bleomycin was used in both animal and airway epithelium models. Male Sprague-Dawley rats were intratracheally instilled with bleomycin or saline (control) followed by nose-only inhalation exposure to CeO₂NP aerosols (diameter of ~ 43 nm) or control for 3 hours per day for 4 days per week for one or two weeks. At three days postexposure, the animals were sacrificed for analysis of bronchoalveolar lavage (BAL) fluid, lung histopathology and global mRNA expression. Comparative in vitro studies were conducted to investigate biological responses at the cellular level, using 3D human small airway epithelium cultures (SmallAir™) exposed to CeO₂NP aerosols (with a diameter of ~ 86 nm) at the air-liquid-interface at deposition doses comparable to those received in vivo in the small airway. Results In vivo, bleomycin treatment resulted in an increase in total BAL cells and fibrotic staining, and significant induction of inflammatory and oxidative stress, as shown by mRNA sequencing analysis. One week of exposure to CeO₂NPs modified these responses by attenuating fibrotic staining and reducing the expression of genes associated with lung function, inflammation and epithelial-mesenchymal transition (EMT). In vitro, CeO₂NP exposure modulated some bleomycin-induced cellular responses, although these models do not fully capture the complexity of whole body and tissue systems, highlighting limitations and considerations for future in vitro exposure studies. Conclusions These findings demonstrate that CeO₂NPs can potentially modulate lung injury responses in the context of active disease, with both potential protective effects and adverse outcomes. Hazard assessment of CeO₂NPs should therefore consider disease status, as their effects may deviate from conventional paradigms of nanoparticle toxicity.