The effect of PM2.5 exposure on lung inflammation and mitochondrial dysfunction using a macrophage-alveolar organoid co-culture system

<bold>Background:</bold> Accumulation of Particulate matter (PM) as small as ≤2.5 microns (PM_2.5) has adverse effects on human health, particularly in respiratory diseases. However, the molecular mechanisms by which PM_2.5 exerts these effects are not fully understood. This study investigated that the effects of PM_2.5 on THP-1-derived macrophage cells and alveolar organoids by micro-trans-well co-cultures system and explored the potential mechanisms. <bold>Methods:</bold> Using bioinformatic analysis, we found that differentially expressed genes (DEGs) to changes in the RNA-sequencing. Moreover, we have functionally validated cell-cell interaction using a co-culture system. <bold>Results:</bold> We observed significant up/down-regulated genes in the diesel-derived PM_2.5 exposed macrophages and alveolar organoids compared with those in the control group. Among the differentially expressed genes (DEGs) in the macrophages, we detected 93 up-regulated genes and 171 down-regulated genes. Using bioinformatic analysis, we found that that down-regulated phagosome and HIF-1 link exposure to PM_2.5. As a result, exposure to PM 2.5 in the co-culture system may cause mitochondrial dysfunction and activate FUNDC and p62, which are related to mitophagy, as demonstrated by relative mRNA and protein expressions. The excess ROS induced by PM_2.5 impaired mitophagy, which is mitochondrial homeostasis. <bold>Conclusion:</bold> Our findings provide some insights into mechanisms' role in respiratory patients' response to air pollutants, which may help the new strategies to attenuate air pollution-associated respiratory diseases.