title: The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis.
abstract: The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock "gated" pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic Clock(Δ19) mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom;
authors.forename: Vanja
authors.initials: V
authors.lastname: Pekovic-Vaughan
authors.forename: Julie
authors.initials: J
authors.lastname: Gibbs
authors.forename: Hikari
authors.initials: H
authors.lastname: Yoshitane
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Dharshika
authors.initials: D
authors.lastname: Pathiranage
authors.forename: Baoqiang
authors.initials: B
authors.lastname: Guo
authors.forename: Aya
authors.initials: A
authors.lastname: Sagami
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: David
authors.initials: D
authors.lastname: Bechtold
authors.forename: Andrew
authors.initials: A
authors.lastname: Loudon
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Jefferson
authors.initials: J
authors.lastname: Chan
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukada
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D024721:E-Box Elements / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D017879:Isothiocyanates / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D013454:Sulfoxides
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D001761:Bleomycin; C016766:sulforaphane; D005978:Glutathione
keywords: NRF2; bleomycin; circadian clock; glutathione; pulmonary fibrosis