Interplay between Airway Smooth Muscle and Airway Epithelium: From Glutamate Metabolism to Epigenetic Reprogramming in Airway HyperresponsivenessSun, Yuchen (2024) Interplay between Airway Smooth Muscle and Airway Epithelium: From Glutamate Metabolism to Epigenetic Reprogramming in Airway Hyperresponsiveness. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractAsthma is a chronic airway disease affecting 330 million individuals globally, characterized by airway inflammation, hyperresponsiveness (AHR), and remodeling. The complexity of asthma stems from the involvement of various airway cells. Key pathological changes include airway epithelial (AEP) apoptosis/autophagy, goblet cell hyperplasia, airway smooth muscle (ASM) proliferation and contraction, and fibroblast activation. Glutamate (Glu) metabolism is known to regulate redox states in various diseases, but its role in asthma remains underexplored, despite the increased oxidative stress in asthmatic airways. Recent evidence suggests that epigenetic mechanisms play a significant role in regulating metabolism-related genes, and vice versa. Glu is metabolically converted to α-ketoglutarate (α-KG), which affects the activity levels of α-KG-dependent epigenetic enzymes like Ten-eleven Translocation (TET) and Histone Lysine Demethylase (KDM). While AEP cells are thought to contribute to ASM remodeling and enhanced AHR, the role of Glu metabolism in these processes is unclear. We hypothesize that epithelial-derived Glu metabolism epigenetically modifies ASM functions, driving airway inflammation and remodeling in asthma. Our study demonstrates that the Glu transporter SLC1A1 is upregulated in asthmatic ASM cells, correlating with elevated intracellular Glu and α-KG levels and increased TET activity. Knockdown of SLC1A1 reversed aberrant phenotypic changes like ASM proliferation and migration, likely through modulating α-KG-dependent TET and KDM4 activity levels and altering DNA hydroxymethylation and histone demethylation at ASM gene promoters. Additionally, we found that IL-13 induced Glu release in AEP cells cultured under air-liquid interface (ALI) conditions, which stimulated ASM growth and proliferation, and increased global DNA hydroxymethylation. These effects were also reversed by knocking down SLC1A1 in ASM cells. Our study reveals how Glu metabolism contributes to epigenetic regulation of airway structural cell functions and identifies SLC1A1 as a target for reversing asthma exacerbation. These findings advance our understanding of the epigenetic mechanisms underlying airway cell function in asthma, suggesting new directions for therapeutic intervention that may ultimately reduce the global disease burden. Share
Details
MetricsMonthly Views for the past 3 yearsPlum AnalyticsActions (login required)
|
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}