Circadian regulation of pulmonary disease: the importance of timing

Abstract

Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms.

Keywords: Lung; asthma; chronic obstructive pulmonary disease; circadian clock; infection; pulmonary fibrosis.

Figure 1. A perfect sinusoid representing a circadian oscillation

The four key parameters have been labelled: MESOR is the baseline of the oscillation; period is the time taken for the oscillation to complete one full cycle; amplitude is the distance from the MESOR (baseline) to the trough (equivalently calculated as the distance from the MESOR to the peak); phase is the time of day associated with the peak of the wave. For this example, MESOR = 0.5, period = 24 h, amplitude = 1.5 and phase = 6 am.

Figure 2. The mechanism of the peripheral oscillator

This oscillates with a 24-h period through a transcription translation feedback loop (TTFL). BMAL1/CLOCK heterodimer drives the transcription of PER and CRY. These proteins then inhibit the BMAL1/CLOCK heterodimer creating a negative feedback loop. Over time PER and CRY degrade, partly through the actions of SIRT1, enabling a new cycle to start. REV-ERB inhibits the transcription of BMAL1 which provides a further level of control to the feedback loop. In contrast ROR activates the transcription of BMAL1 antagonising the action of REV-ERB (REV-α = REV-ERBα; REV-β = REV-ERBβ; E-box = enhancer box DNA response element; RORE = RAR-related orphan receptors response element).

Figure 3. Cell types involved in pulmonary circadian pathology

In the lung, circadian effects can be mediated through different cell types, dependent upon the underlying disease. For instance, the peripheral oscillator regulates eosinophil chemotaxis a key determinant of eosinophilia, a marker of severe asthma. Inflammatory responses to cigarette smoke, a key aetiological agent in COPD, is under circadian control in the club cell. Fibroblast/ myofibroblast differentiation, partly responsible for the deposition of collagen in pulmonary fibrosis, is also under circadian control. Phagocytosis of bacteria by macrophages is also regulated by the peripheral oscillator, which is important in pneumonia. Therefore, circadian regulation of pulmonary pathophysiology is mediated through several different cell types and mechanisms.

Figure 4. Circadian regulation of the pathophysiology of asthma

Asthma is characterised by airway constriction and inflammatory cell influx leading to airway hyperresponsiveness and airway remodelling associated with smooth muscle hypertrophy, goblet cell metaplasia, and accumulation of myofibroblasts and collagen. Type 2 inflammation is initiated by an adaptive immune response due to exposure to allergen, stimulating T-Helper 2 (TH2) cells and Innate Lymphoid group 2 (ILC2) cells to secrete interleukins (IL)- 4, 5, and 13. IL-4 stimulates the production of allergen specific IgE antibodies from B cells causing mast cell activation and degranulation leading to secretion of histamine, IL-3, 4, 5, 9, and prostaglandin D2 (PGD2). IL-13 aggravates AHR, stimulates goblet cells to produce mucus and airway epithelial cells to produce cytokines/chemokines for eosinophil recruitment. IL-5 secretion leads to eosinophil trafficking which is regulated by the clock and demonstrates a time-of-day effect. Non-type 2 inflammation also occurs in asthma, through activation of the innate immune response resulting in T-Helper 1 (TH1) and T-Helper 17 (TH17) cells leading to neutrophil recruitment. Figure adapted based on Durrington et al., 2018 [44], Lloyd et al., 2001 [35], Gibbs et al., 2009 [16], and Israel et al., 2017 [143].

Figure 5. Circadian rhythms in clinical asthma

Symptoms of asthma worsen during the night, peaking around 04:00 [45]. This is mirrored by a corresponding decrease in lung function (shown here as peak flow) and increase in sputum and blood eosinophils both at 04:00 [44]. Lung function is highest at 16:00 [44,45]. Fractional exhaled nitric oxide (FeNO) also shows a diurnal variation, peaking at 10:00 [47].