Late Breaking Abstract - The club cell circadian clock regulates airway barrier integrity

<bold>Background:</bold> The club cell (CC) circadian clock has been identified as a key local regulator in the lung, potentially driving many of the inflammatory responses experienced by patients with asthma. The CC circadian clock is driven by BMAL1 expression, which promotes the expression of Reverba, a potential novel target for improving airway barrier function. <bold>Methods:</bold> Airway epithelial cells (AECs) were isolated from male C57BL/6, wild type (WT) and CCSP-BMAL1 knock out (KO) mice (lacking a functional CC clock). Cells were grown in air liquid interface cell culture to produce 2-D lung organoids which were then examined for epithelial barrier function, using transepithelial electrical resistance (TEER) measurements, every 4hrs over 96hrs, at baseline, +/- IL13, +/- Reverba ligand SR9009. <bold>Results:</bold> TEER values from WT AECs show a daily pattern of rhythmic fluctuations in tightness, suggesting that tight junction function is naturally rhythmic in the lung. This rhythmicity was abolished when BMAL1 was knocked out of the CCs in the lung. Furthermore, IL13 exposure dampens the rhythmicity in the airway barrier and lowers its integrity. Finally, when dosed with SR9009, a Reverba ligand, barrier integrity is improved especially in KO cells. <fig><object-id>erj;64/suppl_68/PA2659/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig> <bold>Perspectives:</bold> The circadian clock mechanism, particularly in CCs, plays an important role in maintaining airway barrier integrity. In the presence of IL13, barrier integrity worsens, but can be improved by targeting Reverba.