37 Attenuation of toxic responses triggered by ultrafine particle overload

Abstract Air pollution remains a major global health threat, consisting of particulate matter (PM), transition metals, and liquid aerosols. Among these, ultrafine particles (PM0.1, <100 nm) are particularly hazardous because of their large surface area, high particle number, and ability to adsorb toxic organic and metallic compounds. Present in both indoor and outdoor environments, PM0.1 can penetrate deep into the alveoli, triggering chronic inflammation and tissue injury. Despite extensive studies, the mechanisms underlying PM0.1 toxicity are still not fully understood. A leading hypothesis is particle overload, in which excessive particulate accumulation within alveolar macrophages reduces their clearance efficiency and motility, leading to persistent inflammation and lung damage. In this study, carbon black and diesel particulate matter (SRM-2975) were used as representative ultrafine particles to compare their pulmonary toxicity. Their physicochemical characteristics were analysed, and a single-dose intratracheal instillation was conducted in mice, followed by a 28-day recovery period to assess lung burden and inflammatory responses. For each particle type, overload- and non-overload-inducing concentrations were established. Transcriptomic profiling was performed to identify molecular pathways associated with exposure, and candidate compounds that enhance particle clearance were screened and tested for protective efficacy. At the cellular level, PMA-differentiated THP-1 macrophages were exposed to the particles. Diesel particles caused minimal cytotoxicity, whereas carbon black induced mild cell damage (∼7% to 8%). Co-exposure with clearance-promoting agents mitigated this effect. These results provide mechanistic insight into ultrafine particle–induced toxicity and support development of therapeutic strategies to reduce health risks from ultrafine particulate exposure.