Airway hyper-responsiveness is regulated by the circadian clock through Rev-erbα. Durrington HJ, Begley N, Krakowiak K, Maidstone R, Loudon A, Ray DW

Background Asthma symptoms show marked circadian variation; being worse in the early morning. Airway resistance shows diurnal physiological variation, which is more exaggerated in asthma. Maximal resistance occurs in the early morning. Using a murine model of asthma we investigated whether the timing of allergen challenge influenced airway hyper-responsiveness (AHR) and allergic inflammation. Rev-erbα provides a gate between the core cellular molecular clock and the immune response. We therefore employed the clock gene knock-out mouse, Rev-erbα-/-. Understanding the chronobiology of asthma may open new treatment opportunities, with new, or existing drugs (chronotherapy). Aims • Does time of day influence the effects of allergen challenge on AHR and inflammation? • Is Rev-erbα important in regulating AHR? Method C57/Bl6 female Rev-erbα-/- mice and littermate control mice (aged 8-12 weeks) were challenged with house dust mite, HDM or PBS daily for 3 weeks at either ZT23 (just before lights come on, 6am) or ZT 11 (just before lights are turned off, 6pm). 24 hours after the last challenge AHR was measured by Flexivent. Mice were then sacrificed and bronchoalveolar lavage performed, lungs and blood were collected. An ANCOVA test was performed to analyse AHR data. Results 1. There is baseline diurnal variation in AHR in C57/Bl6 mice. AHR measured at ZT11 is significantly greater than when measured at ZT 23 Figure 1a. 2. HDM challenge at ZT 11 causes significantly greater AHR, compared to HDM challenge at ZT23 Figure 1a. 3. In Rev-erbα-/- mice, baseline diurnal variation in AHR was reversed compared to littermate controls. AHR at ZT23 was greater than at ZT11 Figure 1b. 4. HDM challenge in Rev-erbα-/- mice resulted in greater AHR compared to littermate controls, however, there was no longer a time of day difference by challenge time Figure 1b. 5. HDM caused significantly increased levels of inflammation in both Rev-erbα-/- and littermate mice. However, there was no difference in inflammatory response by time of day in either Rev-erbα-/- or littermate mice. Discussion • The circadian phenotype in asthma may be driven through diurnal changes in AHR independent of inflammatory changes. • The circadian gating of AHR in asthma appears to be dependent upon the action of Rev-erbα • In nocturnal mice, AHR increased at ZT11 (6pm), corresponding to the start of the active phase in humans (morning, 6am) • Further work is underway to determine how the circadian clock controls AHR to methacholine.

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