Background: We have previously shown that the molecular clock protein, REV-ERB?, is important in determining time of day variation in airway hyperresponsiveness (AHR) in a Rev-erb? 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-erb? 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-erb? in AHR.

Figure 1: Mid EF50 variation by time of day.