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Circadian asthma airway responses are gated by REV-ERBα.
Durrington, Hannah J; Krakowiak, Karolina; Meijer, Peter; Begley, Nicola; Maidstone, Robert; Goosey, Laurence; Gibbs, Julie E; Blaikley, John F; Gregory, Lisa G; Lloyd, Clare M; Loudon, Andrew S I; Ray, David W.
Afiliação
  • Durrington HJ; Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK Hannah.durrington@manchester.ac.uk.
  • Krakowiak K; Wythenshawe Hospital, University Hospital of South Manchester, Manchester University NHS Foundation Trust (MFT), Manchester, UK.
  • Meijer P; Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Begley N; Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Maidstone R; Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Goosey L; Division of Informatics, Imaging and Data Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Gibbs JE; Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Blaikley JF; Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Gregory LG; Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Lloyd CM; Wythenshawe Hospital, University Hospital of South Manchester, Manchester University NHS Foundation Trust (MFT), Manchester, UK.
  • Loudon ASI; National Heart and Lung Institute, Imperial College, London, UK.
  • Ray DW; National Heart and Lung Institute, Imperial College, London, UK.
Eur Respir J ; 56(6)2020 12.
Article em En | MEDLINE | ID: mdl-32586876
ABSTRACT

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).
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asma / Relógios Circadianos Limite: Animals Idioma: En Revista: Eur Respir J Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asma / Relógios Circadianos Limite: Animals Idioma: En Revista: Eur Respir J Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido