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bioRxiv · 10.64898/2026.05.20.726480

Cigarette Smoke Extract (CSE) reduces expression of functional TRPV4 channels in primary human bronchial epithelial cells differentiated at an Air Liquid Interface (ALI) in vitro

Mueller, I.·Alt, P.·Gudermann, T.·Kiefmann, M.·Dietrich, A.
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Abstract

Primary human bronchial epithelial cells (pHBECs) of the airways of smokers are chronically exposed to cigarette smoke, which may induce chronic obstructive pulmonary disease (COPD) ranked fourth among the most common global causes of death. Using an established protocol for differentiation of pHBECs to a pseudostratified epithelium at an air liquid interface (ALI), we analyzed functional expression of transient receptor potential vanilloid 4 (TRPV4) proteins after application of cigarette smoke extract (CSE), which upregulated seven smoke exposure regulated genes (SERGs). TRPV4 protein expression in the plasma membrane and localization next to the cilia of ciliated cells was reduced, while cell barrier function was not altered after chronic exposure to CSE for 28 days compared to untreated control cells. Accordingly, TRPV4-mediated Ca2+ influx was blocked in pHBECs after CSE exposure. Moreover, Os-9 protein, which after binding mediates protection from degradation of TRPV4 protein by polyubiquitination, was significantly less expressed in pHBECs upon CSE exposure. Most interestingly, overexpression of OS-9 in pHBECs rescued reduced TRPV4 protein levels induced by CSE. Our study identifies a novel molecular mechanism of toxicity by CSE interfering with TRPV4 and OS-9 expression in pHBECs, which may blaze the trail for new therapeutic options in COPD.

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Mueller, I., Alt, P., Gudermann, T., Kiefmann, M., Dietrich, A.. 2026-05-22. Cigarette Smoke Extract (CSE) reduces expression of functional TRPV4 channels in primary human bronchial epithelial cells differentiated at an Air Liquid Interface (ALI) in vitro. https://doi.org/10.64898/2026.05.20.726480

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