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Circadian Timing in the Lung; A Specific Role for Bronchiolar Epithelial Cells

Faculty of Life Sciences and ESRG (J.E.G., S.B., D.W.R., A.S.I.L.), University of Manchester, Manchester M13 9PT, United Kingdom; North West Lung Centre (J.P., D.S.), Wythenshawe Hospital, University of Manchester, Manchester M23 9LU, United Kingdom; and Discovery Biology (S.F.), Respiratory CEDD, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom

Address all correspondence and requests for reprints to: Professor Andrew Loudon, Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester M13 9PT, United Kingdom. E-mail: andrew.loudon{at}manchester.ac.uk.

In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology.