LSC - 2020 - Diesel exhaust particles alter mitochondrial bioenergetics in human bronchial epithelial cells

Diesel exhaust particles (DEP) causes air pollution and is envisioned as cause for lung disorders including COPD. DEP induces inflammation and reactive oxygen species (ROS), linked to mitochondrial dysfunction. Bronchial epithelial cell damage drives epithelial-to-mesenchymal transition (EMT) and fibrosis, processes sensitive to cAMP. Exchange proteins directly activated by cAMP (Epac’s) are mediators of fibrosis and inflammation. Epac’s expression (function) is altered by oxidative stress. Epac’s role in DEP induced lung injury is unknown. BEAS-2B cells were exposed to different concentrations (= 300 µg/ml) of DEP = 72h. Markers: inflammation (IL-8 (CXCL8), IL-8, IL-6), oxidative stress (thioredoxin (TXN), heme oxygenases (HMOX1/2), HIF1A, GPX1, CAT), mitochondrial activity (Nrf1, SOD1/2/3)), mitochondrial shape (mitotracker), viability, metabolism (Seahorse), cAMP (Epac’s), EMT (NRF1, E-cadherin), cell migration (wound healing, xCelligence). DEP increased CXCL8 and IL-6, not IL-8. DEP induced HMOX1 not HMOX2 or HIF1A; enhanced TXN and SOD2 but decreased GPX1. CAT and SOD1 were unchanged. DEP reduced cell viability. NRF1 was up- and E-cadherin reduced. DEP delayed wound healing and BEAS-2B cell adherence. DEP changed mitochondria morphology, reduced mitochondrial bioenergetics (respiration, ATP, spare capacity). Next, DEP induced transient alterations in cAMP, and Epac’s expression. DEP change inflammation, ROS handling, accompanied by EMT-like features. DEP alters mitochondrial bioenergetics and cAMP dynamics evidenced by alterations in the abundance of both Epac’s. Currently, we pharmacologically target Epac’s to restore mitochondria bioenergetics in experimental models of DEP.