Adverse outcome pathway of ambient fine particulate matter-induced respiratory toxicity: role of non-coding RNAs

Fine particulate matter (PM<sub>2.5</sub>) exposure has been recognized as one of the risk factors for chronic obstructive pulmonary disease (COPD). With increased PM<sub>2.5</sub>-related research, the mechanism of PM<sub>2.5</sub>-induced toxicity suggests the role of non-coding RNA (ncRNA) in this process; however, a comprehensive framework to link PM<sub>2.5</sub> exposure with COPD remains vacant. The adverse outcome pathway (AOP) framework integrates research from different models to achieve a systematic assessment of PM<sub>2.5</sub> toxicity in the respiratory system. This review focused on PM<sub>2.5</sub>-related pathology of COPD at molecular, cellular, organic, individual and population levels using the AOP framework. Combined with our previous studies, the AOP-Wiki website, and other available evidence, we established an AOP framework in which the molecular initiating event is the alteration of ncRNA expression profiles. Subsequently, oxidative stress and activation of the inflammatory pathway induced pulmonary inflammation, epithelial-mesenchymal transition, fibroblast proliferation, and myofibroblast differentiation, leading to airway remodeling, pulmonary epithelial cell apoptosis, and emphysema caused by autophagy. These were identified as key events. They collectively contribute to the pathogenesis of COPD by altering the structure and function of the airways and lung tissue, thus exacerbating respiratory symptoms and disease progression. This framework will provide a reference to identify biomarkers of PM<sub>2.5</sub> exposure-triggered respiratory diseases.