Circadian rhythm changes can affect lung function, introducing susceptibility to infection and other adverse effects on health and disease.
What does the Circadian Rhythm do?
The circadian rhythm regulates many physiological parameters including lung function, immune responses, and cardiopulmonary function. The master circadian pacemaker is located in the anterior of the hypothalamus, also called the suprachiasmatic nuclei (SCN). The SCN receives inputs from environmental cues, such as light and temperature and modulates downstream vital biological functions in an oscillatory fashion.
What are the effects of the circadian rhythm on lung function?
The lung contains its own autonomous peripheral circadian clock mechanisms and synchronizes with signals originating from the core oscillator. Disruption of the central and/or peripheral endogenous clocks can negatively effect health and exacerbate disease severity.
The central and peripheral clocks use a common set of cellular feedback loops to regulate 24-hour biological oscillations. Clara cells in the bronchioles play a major role in the diurnal variation of lung physiology1. These physiological oscillations are driven by the rhythmic activation and repression of transcriptional factors and genes such as CLOCK, BMAL1, PER, CRY and REV-ERBα.
In mammals, pulmonary function follow day-night patterns. Meaning, that the peak in respiratory function is at mid-day and a trough occurs at night. Additionally, it has been well documented that certain symptoms of respiratory disease become more severe at night. This diurnal variation in symptom severity seems to be the crosstalk between the peripheral lung clock and immune cells, in which REV-ERBα is heavily implicated2.
In addition, circadian rhythm disruption negatively impacts pulmonary function in a sexually dimorphic manner. Hadden et al.3 found that chronic jet lag (CJL) resulted in increased resistance in the large conducting airways (Newtonian Resistance; Rn), with male mice significantly more affected than females.
Techniques to measure the effects of the circadian rhythm on lung function.
Measuring the effects of the circadian rhythm on the lung requires the highest possible sensitivity to capture crucial details about the mechanical properties of airways. The flexiVent is able to measure mechanics of the lungs as a whole, and partition between central vs. peripheral airways. Moreover its automated dose-response feature permits an unparalleled level of insight into lung function throughout the progression of inflammation, infection, or disease development.
Circadian Rhythm effects lung function of different pulmonary diseases.
- Nocturnal Asthma shows symptoms such as air flow limitation, airway hyperresponsiveness and an increase in the infiltration of specialized immune cells such as eosinophils4.
- Recent studies show REV-ERBα plays a pivotal role in regulating Airway Hyperresponsiveness (AHR) in murine models of allergic asthma. For example, Durrington et al5 developed a House Dust Mite (HDM) model in a REV-ERBα knock out mouse to investigate the role of REV-ERBα in mediating allergic asthma. Overall findings showed that knocking out REV-ERBα resulted in significantly greater AHR, in terms of dynamic resistance as measured by the flexiVent, when compared to controls.
- Patients with COPD also display rhythmic variation in pulmonary function, including significantly reduced forced vital capacity (FVC), forced expiratory volume (FEV) and peak expired flow (PEF) at night6.
- Animal models of cigarette smoke-induced COPD have shown disruption of circadian clock function and decrease in lung function parameters such as resistance, compliance and flow limitation (FEV/FVC)7.
Read more publications featuring the flexiVent and other SCIREQ research systems.
1 Gibbs, J.E., Beesley, S., Plumb, L., et al. (2009). Circadian Timing in the lung; a specific role of bronchiolar epithelial cells. Endo ;150:268–76
2 Gibbs, J.E., Blaikley, J., Beesley, S., et al. (2012) The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. PNAS;109:582–7.
3 Hadden, H., Soldin, S.J., and Massaro, D. (2012). Circadian disruption alters mouse lung clock gene expression and lung mechanics. J Appl Physiol., 113: 385-392
4 Kraft, M., Martin, R.J., Wilson, S., Djukanovic, R., & Holgate, S.T. Lymphocyte and Eosinophil Influx into Alveolar Tissue in Nocturnal Asthma. Am J Respir Crit Care Med, 159: 228-234
5 Durrington, H., et al. (2018). Airway Hyper-Responsiveness is Regulated by the Circadian Clock through REV-ERBα. American Journal of Respiratory and Critical Care Medicine, 197: A7272
6 Borsboom, G. J., et al. Diurnal variation in lung function in subgroups from two Dutch populations: consequences for longitudinal analysis. American journal of respiratory and critical care medicine 159, 1163–1171 (1999).
7 Hwang, J. W., Sundar, I. K., Yao, H., Sellix, M. T., Rahman, I. (2014). Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway. FASEB. J 28, 176–194