Airway inflammation and hyperresponsiveness in asthma is regulated by the circadian clock through REV-ERBα

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Background: We have previously shown that the molecular clock protein, REV-ERBα, is important in determining time of day variation in airway hyperresponsiveness (AHR) in a Rev-erbα global knock out murine model of allergic airway disease (AAD). However, it is unclear which peripheral clock governs this response. Aim: To determine if the peripheral molecular clock in the lung, regulates AHR. Methods: Using the Cre-lox system we generated mice with Rev-erbα deleted in CCSP expressing airway epithelial cells (CCSP-Rev-erba-/-, KO) & employed a 5-wk AAD model using i.n HDM. AHR was measured by increasing methacholine concentration both non-invasively (DCP, SciReq) every 6 hours & invasively (FlexiVent) followed by an analysis of immune cells & lung pathology. Results & Discussion: Preliminary analysis shows, Tidal mid-expiratory flow (EF50) was reduced & varied by time of day in HDM WT mice compared to PBS control (p=0.007, ANOVA). In HDM WT mice, EF50 decreased, reaching a trough between 1900 & 0100. In comparison to WT mice, KO mice showed baseline reduced EF50 (PBS treated) across the day and HDM treated KO mice lost time of day variation in EF50 (Figure 1). Conclusion: AHR is regulated by the molecular clock present in the bronchial epithelial cell of airways. Ongoing investigation of immune cells & pathology will further elucidate the role of Rev-erbα in AHR. Figure 1: Mid EF50 variation by time of day.

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