| 摘要: | Adverse health effects, including chronic obstructive pulmonary disease (COPD), have been previously reported by air pollution exposure. However, there is limited data on the molecular mechanisms underlying the emphysema development in COPD by air pollution. The role of metals in particulate matter (PM) and their impact on lung changes and gene expression in COPD also remain unclear. To investigate the effects of air pollution exposure on emphysema development, we used 1.5-year-old Fischer 344 rats exposed to traffic-related air pollution with or without HEPA filtration for 3 months. We also used type II alveolar epithelial cells (AECII) MLE-12 exposed to traffic-related diesel exhaust particles (DEP) to investigate the Hippo signaling pathway. We also examined human lung sections from non-smokers, smokers, and COPD subjects to confirm the Hippo pathway involvement. Air pollution exposure led to the deposition of 52.05% particulate matter of < 2.5 ?m in aerodynamic diameter (PM2.5) in the alveoli, decreasing lung function and increased emphysema, airway wall thickening, and inducible bronchus-associated lymphoid tissue (iBALT) formation in rats. The level of Co in the lung was positively correlated with lung function. DEP exposure dysregulated Hippo pathway and induced oxidative stress responses in AECII. Air pollution exposure decreased cell adherens junctions and YAP phosphorylation while increasing TAZ phosphorylation, AECII-to-AECI differentiation and cellular senescence in AECII. Smoking subjects with pre-COPD exhibited decreased YAP phosphorylation in AECII compared to COPD subjects, suggesting an increased risk of emphysema progression. Next, we used C57Bl/6JNarl and pre-treated B6.Sftpc-CreERT2;Ai14(RCL-tdT)-D mice exposed to DEP and soluble iron (FeCl3) and treated with ITIH4 to investigate the role of metals in particulate air pollution-induced lung changes. DEP and Fe exposure increased neutrophils, with DEP also increasing eosinophils. ITIH4 treatment reduced the inflammatory cells by DEP and Fe, as well as the severity of lung damage, inflammatory cytokine levels, and oxidative stress. Inflammatory cells in BALF and the Fe and single-cell Fe content in peripheral blood mononuclear cells (PBMC) were correlated with changes in lung mechanics. ITIH4 treatment increased cell adherens protein and YAP/TAZ phosphorylation, while decreasing cell senescence and autophagy in lung. We investigated gene expressions in COPD and asthma subjects using publicly available datasets. Asthma subjects represented eosinophilic inflammation, while COPD subjects represented neutrophilic inflammation. We also investigated RNA sequencing in PBMC and metals of bulk PBMC and single-cell Fe content in PBMC of COPD subjects. Distinct genotyping patterns were observed, with secretory granule gene sets increased in PBMC of COPD and T cell-mediated and mucosal immune response gene sets increased in sputum and airway epithelia of asthma subjects. Decreased expression of PDPN in PBMC of COPD subjects and ITIH4 in sputum and airway epithelial samples asthma subjects were observed. Hippo pathway-related gene expressions changes, increased inflammatory cell chemotaxis, and IL-17 and TNF signaling pathways were found in PBMC and lung tissue of COPD subjects, along with gene diseases related to lung, tooth, and pulmonary fibrosis. Decreased levels of arsenic in PBMC and zinc in red blood cells were found in COPD subjects. The gene expressions of CTNNA1, SFTPC, LGALS3, and SIRT1 in the Hippo pathway were correlated with metals in PBMC of COPD. The expression of autophagy-related gene MAP1LC3B showed a positive correlation with lead levels in PBMC of COPD subjects. In conclusion, air pollution exposure contributes to emphysema development through the involvement of the Hippo pathway. Different physicochemistry of particulate air pollution result in distinct inflammatory cell profiles, and ITIH4 treatment alleviated the inflammation. Changes in trace metal levels in PBMC affect gene expressions that potentially contribute to phenotypic changes associated with COPD. These findings shed light on the interactions between genes, proteins, and metals in particulate air pollution, which contribute to phenotypic changes and lung diseases. This knowledge can significantly impact the development of preventive strategies and personalized interventions aimed at mitigating the risk of emphysema progression in individuals with COPD. |
