Pt - 杂志Au - Durrington，Hannah J. Au - Krakowiak，Karolina Au - Meijer，Peter Au - Begley，Nicola Au - Maidstone，Robert Au - Goosey，Laurence Au - Gibbs，Julie E. Au - Blaikley，John F.AU - Gregory, Lisa G. AU - Lloyd, Clare M. AU - Loudon, Andrew S.I. AU - Ray, David W. TI - Circadian asthma airway responses are gated by REV-ERBα AID - 10.1183/13993003.02407-2019 DP - 2020 Dec 01 TA - European Respiratory Journal PG - 1902407 VI - 56 IP - 6 4099 - //www.qdcxjkg.com/content/56/6/1902407.short 4100 - //www.qdcxjkg.com/content/56/6/1902407.full SO - Eur Respir J2020 Dec 01; 56 AB - Background The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control.Objectives To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα.Methods After exposure to the intra-nasal house dust mite (HDM) allergen challenge model at either dawn or dusk, AHR to methacholine was measured invasively in mice.Main results Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both in vivo and ex vivo, in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene Rev-erbα, indicating that such effects on asthma response are likely to be mediated via the circadian clock. We suggest that muscarinic receptors one (Chrm 1) and three (Chrm 3) may play a role in this pathway.Conclusions We identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion.Clinical implication These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy).REV-ERBα gates airway hyper-responsiveness by time of day. Future asthma therapies should aim to dose anti-muscarinic agents at the most efficacious time of day (chronotherapy) and modulate the molecular clock https://bit.ly/37qY4sC