Circadian Disruption in Night Shift Work and its Association with Pulmonary Disease

Abstract

Globalization and the expansion of essential services over continuous 24-hour cycles have necessitated the adaptation of the human workforce to shift-based schedules. Night shift work (NSW) causes a state of desynchrony between the internal circadian machinery and external environmental cues, which can impact inflammatory and metabolic pathways. The discovery of clock genes in the lung has shed light on potential mechanisms of circadian misalignment in chronic pulmonary disease. Here, we review the current knowledge of circadian clock disruption caused by NSW and its impact on lung inflammation and associated pathophysiology in chronic lung diseases such as asthma, COPD, pulmonary fibrosis, and COVID-19. Furthermore, we discuss the limitations of the current understanding of circadian disruption and potential future chronotherapeutic advances.

Introduction

Economic demands and extension of essential services to general populations require a continuous human workforce leading to 20–30% of the workforce undertaking shift work (SW) (1). SW denotes work schedules that divide 24-h into roughly similar durations allowing teams of different individuals to alternate between early morning, afternoon, and night. More than 75% of the SW population experiences chronic sleep deprivation, poor quality of sleep, or sleep disorders (2). Circadian misalignment, arising due to the desynchrony of external light cues and internal circadian machinery, can accelerate detrimental metabolic change and increase the risk of respiratory infections (3–6). Sleep deprivation can affect the transcription of genes involved in circadian rhythms, sleep homeostasis, oxidative stress, and metabolism (7). Sleep restriction to just six hours has been shown to upregulate genes involved in tumorigenesis, chronic inflammation, and cardiovascular disease and downregulate genes involved in immune function (7).

The identification of peripheral clock genes in the lung and recent evidence on circadian variability of the pulmonary disease have implored the question of the effect of night shift work (NSW) on these pathologies. NSW showed significantly worse outcomes, poorer lung function, and a higher prevalence of the disease in individuals with obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD) when compared to day shift work (8–11). Restrictive airway diseases like pulmonary fibrosis (PF) were also associated with SW (12). The role of circadian clock genes in key inflammatory and immune pathways is evident, and alterations in the core clock genes at the transcriptional and/or translation level can further increase the risk of developing chronic pulmonary diseases (13, 14).

In this review, we highlight the current evidence on the impact of NSW and its close association with chronic lung disease progression. Additionally, we cover recent literature specific to SW exaggerating chronic lung diseases such as asthma, COPD, PF, and COVID-19. Finally, we provide insights into the role of circadian clock genes in inflammatory pathways, including limitations of the current understanding of NSW and pulmonary disease, and conclude with possible chronotherapeutic advancements moving forward into the future.

Understanding the mammalian biological clock machinery

The endogenous circadian clock in mammals consists of a centrally operating ‘master clock’ in the suprachiasmatic nucleus (SCN), which regulates independent self-sustaining peripheral clocks residing in virtually every cell type, including skin, gut, airways, and immune system. External visual cues like light stimulate the retinohypothalamic tract, which synchronizes the SCN with the external environment via the cAMP response element-binding (CREB) protein. The SCN exerts a regulatory effect on the peripheral clocks through hormonal (melatonin from the pineal gland or cortisol from the hypothalamus-pituitary-adrenal axis) and neuronal (sympathetic and parasympathetic activity) influence and thereby ensures circadian synchrony across various cell types. At a cellular level, the 24-h physiology of the circadian clock is maintained by interlocking autoregulatory transcriptional-translational feedback loops (TTFLs) (15).

In this review, we will primarily focus on the circadian clock machinery in the lung (13, 14). The Periods (Per1/2/3) and Cry1/2 are essential genes that regulate circadian machinery. Three TTFLs tightly regulate the transcription of these genes. The first core loop comprises the circadian locomotor output cycles kaput (CLOCK) and Brain and muscle ARNT-Like 1 (BMAL1) master regulators. These two proteins form a heterodimer directly binding to the E-box enhancer region to transcribe the Per and Cry genes. During the day, the CLOCK:BMAL1 heterodimer drives the transcription of the Per(s) and Cry(s) which then translocate into the cytoplasm. As the day progresses, translation of the PER(s) and CRY(s) leads to dimerization. The dimerized PER:CRY protein translocates back into the nucleus and represses the transcriptional activity of the CLOCK:BMAL1 heterodimer, ultimately leading to a reduction in PER and CRY proteins. In parallel, the ubiquitin-proteasome pathway enzymatically degrades the protein dimer in the cytoplasm. Eventually, as the PER and CRY proteins reduce, the transcriptional activity of the CLOCK:BMAL1 heterodimer is restored, and Per and Cry are transcribed again. The second feedback loop comprises the two nuclear receptors REV-ERBα/β and Retinoic acid-related orphan receptors (RORα/β/γ) transcribed from the same E-box promotor region of the CLOCK:BMAL1 heterodimer. These nuclear receptors bind to the DNA sequence called ROR response element (RORE) in the Bmal1 gene promoter and regulate Bmal1 expression in anti-phase oscillation to the Per gene expression. The third feedback loop utilizes proteins from the first DBP (D-box binding protein) and second loop NFIL3 (Nuclear Factor Interleukin 3 regulated) to competitively bind to the D-box promotor gene and regulate the expression of Per and Ror genes (16) (Figure 1).

Figure 1: Circadian clock machinery in the lung.

The schematic representation of the transcriptional-translational feedback loop (TTFL) system drives the periodic oscillation of circadian clock genes and proteins at the cellular level in the lung. The TTFL system is divided into three-loop systems, which interact with each other through transcriptomic products. Details of this regulatory system can be found in the section ‘Understanding the mammalian biological clock machinery‘. This figure was partly created using Servier Medical Art (smart.servier.com). Abbreviations: BMAL1- Brain and muscle ARNT-Like 1, CLOCK- Circadian locomotor output cycles kaput, CRY-Cryptochrome, PER- Period, DBP- D-box binding protein, NFIL3- Nuclear Factor Interleukin 3 regulated, ROR- Retinoic acid-related orphan receptor.

Circadian clock and inflammation

To understand the role of circadian disruption in pulmonary inflammation, it may be helpful to review existing literature on inflammatory and immune effects of clock genes using knockout models. As discussed earlier, Per1/2/3, Cry1/2, REV-ERBα/β, and RORα/β/γ are the core clock genes transcribed by the CLOCK:BMAL1 heterodimer in the nucleus of mammalian cells. BMAL1 has been shown to control the mRNA expression of Nrf2 which in turn plays a crucial role in inflammation by suppressing reactive oxygen species (ROS) formation and repression of IL-1β and IL-6 (17). The loss of BMAL1 in macrophages was also found to confer protection in pneumococcal pneumonia (18). REV-ERBα was shown to act as a repressor of pro-inflammatory cytokine IL-6 (19). Another study showed REV-ERBα can modulate the inflammatory function of macrophages by regulating CCL2 expression (20). REV-ERBα can also bind to RORE in Th17 cells and inhibit the expression of IL-17 (21). The deletion of RORα in human monocytes was found to result in the increased expression of TNF, IL-1β, and IL-6 (22). A decrease in Rorα transcription was associated with increased susceptibility to endotoxin-mediated damage and an increase in interleukins such as IL-1β and IL-6 production, leading to increased neutrophil recruitment and neutrophil-mediated damage. Furthermore, RORα plays a pivotal role in the upregulation of Th17, which is recruited as a host defense response to microbes. A decrease in Rorα transcription can lead to a reduced IL-17, IL-21, and IL-22 in the epithelial barrier, increasing the susceptibility to infection (22–24). In another model, REV-ERBα agonism decreased IL-6 production by binding to the promoter region of IL-6 and interfering with its transcription (19, 20). Cry1/2 double KO mice show increased activation of NF-κB signaling-mediated pro-inflammatory cytokines TNFα, and IL-6 (25). An increase in cytokines and recruitment of immune cells including neutrophils, alveolar macrophages, and T lymphocytes can lead to oxidative stress which plays a key role in driving lung parenchymal damage and COPD-like phenotype (26). These findings strongly support the direct regulation of key inflammatory pathways by core circadian clock molecules that contributes to the pathobiology of chronic inflammatory lung diseases.

Circadian clock disruption in Night shift work

Light is one of the most potent ‘zeitgeber’ or time-cue for the human body and can cause circadian phase advances or delays depending on exposure time (27). Circadian disruption through SW results from the misalignment of internal circadian rhythms and external environmental factors. The abrupt changes in the sleep-wake and light-dark schedules result in the displacement of the nadir of cortisol, the peak of melatonin, and the trough of body temperature from the typically occurring first, middle, and last third of nocturnal sleep, to coincide with the wake periods of NSW (28–30). Various studies have investigated the circadian regulation of the human transcriptome using forced desynchrony and sleep deprivation models (7, 31). One study observed that during NSW, 73% of circadian transcripts remained oscillating with a similar phase with habitual bedtimes with reduced amplitudes (32). Only 3% of permanent NSWs have been found to adapt their endogenous melatonin rhythms to night work, leaving most of the population unadjusted to forced circadian desynchrony (33). The transcriptomic activity of peripheral clock-controlled genes (CCG) in association with NSW has gained more research interest recently. Studies showed significant progressive phase delays and dampening in Per1 and Bmal1 expression in PBMCs associated with NSW (32, 34). The effect of NSW on CCG expression was even observed in hair follicles with a significant phase delay in their rhythmicity in rotating NSWs (35, 36). Interestingly, another study showed that Per1/2/3 and Rev-erbα lost their rhythmicity after seven days of NSW in the oral mucosal tissue (37).

The effect of forced circadian desynchrony on inflammation has been evident in murine models. By mimicking conditions of chronic jet lag, another trigger for circadian disruption, rodents had a marked reduction in longevity, increased risk of cancer development, weight gain, impaired glucose tolerance, and diabetes mellitus. A significant decrease in Per2 and Bmal1 expression in Natural Killer (NK) T cells was also observed in a similar chronic shift lag mouse model (38). A recent study showed circadian rhythm disruption caused by weekly alternating light-dark cycles (12-hour shifts) resulted in a two-fold increase in atherosclerotic lesion size, severity, and increased inflammatory markers and oxidative stress (39). This finding was congruent with other studies with simulated phase delays using dim light, which demonstrated increased inflammatory response. Circadian clock disruption is not limited to its effect on inflammation and immune regulation. Chronic desynchrony between endogenous circadian rhythms and the environment can also negatively impact energy metabolism, cardiac remodeling, and cardiac rate and conduction (40–42). Interestingly, some of these studies from in vivo models show preservation of internal synchrony across the central and peripheral clock oscillators in non-24-h light-dark cycles and, in extension, NSW (43). Sleep deprivation is frequently observed in NSWs due to erratic schedules. Reduced sleep has been found to have detrimental effects on the transcription of crucial genes involved in circadian rhythmicity, sleep homeostasis, oxidative stress, and metabolism (7) (Table 1).

Table 1:

Genes altered at the transcription level by sleep deprivation.

Sl.No.	Signaling pathways or cellular processes affected	Target Genes
1	Circadian Rhythms	Clock, Cry2, Per1, Per2, Per3, Nr1d1, Nr1d2, Rora, Dec1, and Csnk1e
2	Sleep Homeostasis	Stat3, Kcnv2, Camk2d
3	Oxidative Stress	Prdx2, Prdx5
4	Metabolism	Slc2a3, Slc2a5, Ghrl, Abca1

Abbreviations: Abca1- ATP binding cassette subfamily A member 1, Camk2d- Calcium/calmodulin dependent protein kinase II delta, Clock- Circadian locomotor output cycles kaput, Cry2- Cryptochrome 2, Csnk1e- Casein kinase 1 epsilon, Dec1- Deleted in esophageal cancer 1, Ghlr- Ghrelin and obestatin prepropeptide, Kcnv2- Potassium voltage-gated channel modifier subfamily V member 2, Nr1d1/2- Nuclear Receptor Subfamily 1 Group D Member 1/2, Per1/2- Period1/2, Prdx2- Peroxiredoxin 2, Ror- Retinoic acid-related orphan receptor, Scl3a2- Solute carrier family 3 member 2, Stat3- Signal transducer and activator of transcription 3

Circadian disruption linking cardiovascular disease and SW has been attributed to the disturbance in normal metabolic and hormonal functions which in association with a higher prevalence of behaviours such as smoking and poor diet, worsen cardiovascular disease outcomes (44). Chronic stress caused by SW can also lead to increased secretion of glucocorticoids and catecholamines, which stimulate the sympathetic nervous system and increase the risk of cardiovascular disease (4). The stressful environment can also disrupt the hypothalamic-pituitary axis and suppress growth hormone and thyroid hormone axis. This in turn can ultimately lead to an increased risk of metabolic syndrome (4, 45).

Night shift work associated with asthma pathophysiology

NSWs were observed to have a 23% higher prevalence of asthma and significantly lower lung functions than day workers (9). The effect of NSW was notably worse for those of morning chronotypes. Peak expiratory flow rate (PEF), when measured in subjects with occupational asthma, was markedly reduced in those working afternoon and night shifts than days (8) (Table 2). A recent study of sewage treatment plant workers observed that those working shift-based schedules had a 24-times higher prevalence of respiratory symptoms such as chest tightness, cough, and exertional breathlessness (46). This study, however, did not study asthmatics in exclusivity. NSW was also a risk factor for chronic spontaneous urticaria, another allergic disorder (47). These studies highlight the circadian rhythmicity of airway physiology and inflammation and the effect of circadian misalignment and sleep deprivation on disease symptomology.

Table 2:

NSW associated with chronic pulmonary diseases and COVID-19 infection.

Pulmonary disease	Region	Sample Size	Major outcome/Key findings	Reference
Asthma	UK	192	ABC (Area between the curve) score was lower in occupational asthma in night shifts and afternoon shifts compared to day shifts. Cross-shift differences PEF were greater in night shift and afternoon shifts compared to day shift workers with occupational asthma.	(8)
Asthma	UK	286,825	Permanent NSWs were 1.36 times more likely to have moderate to severe asthma (OR 1.36, 95% CI 1.03–1.8) and 1.23 times more likely to have all asthma (OR 1.23. 95% CI 1.03–1.46) compared to day workers. Morning chronotypes working irregular shifts had a significantly higher risk of moderate to severe asthma (OR 1.55, 95% CI 1.06–2.27). Permanent NSWs had a higher likelihood of having <80% FEV1 lung functions compared to day workers (OR 1.20, 95% CI 1.03–1.41).	(9)
COPD	UK	286,825	Workers employed day shifts (0.81%) had a lower prevalence of COPD compared to workers employed in shift work without nights (1.26%), irregular shift works including nights (1.27%), and permanent NSW (1.23%).	(9)
Pulmonary fibrosis	UK	500,074	Shift work (OR 1.353, 95% CI 1.069–1.710) and evening chronotype (OR 1.040, 95% CI 1.001–1.080) were associated with pulmonary fibrosis.	(12)
COVID-19	UK	284,027	Individuals employed in irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular NSW (OR 3.04, 95% CI 2.37 to 3.9), and permanent NSW (OR 2.49, 95% CI 1.67 to 3.7) were associated with COVID-19 positive tests compared to individuals not employed in shift-based work.	(79)
COVID-19	UK	10,772	Individuals working night shifts less than once a week (OR 1.81, 95% CI 1.61–2.02) and individuals working weekly night shifts or permanent night shifts (OR 1.54, 95% CI 1.35–1.76) had a significantly higher risk of COVID19 infection compared to those workers not employed in night shifts.	(80)
COVID-19	Netherlands	26,051	NSWs had a 37% higher risk of testing positive for SARS-CoV-2 (HR 1.37, 95% CI 1.05–1.77)	(81)
COVID-19	UK	18,221	NSWs were 1.85 times more likely to be tested positive for COVID-19 infection (OR 1.85, 95% CI 1.42–2.41).	(82)
COVID-19	UK	235,685	Shift workers (OR 2.06, 95% CI 1.72–2.47) and health care workers working shifts (OR 7.67, 95% CI 3.86–14.79) had higher odds of severe COVID-19 infection compared to those not working shifts or in healthcare.	(83)

Nearly three-quarters of the population suffering from asthma report worsening symptoms in the night or early morning (48). The increased muscarinic receptor expression and potency of allergen response and the lower level of serum cortisol and noradrenaline during the night and early morning have partly explained this phenomenon (49, 50). Recent insights into molecular clock genes’ role in pulmonary disease have helped us further expand our understanding of asthma pathophysiology and chronobiology. Compared to healthy controls, bronchial brushings from asthmatics showed a significant reduction in Bmal1, Per3, Dbp, and Nr1d1/2 gene expression (51). Murine experiments using KO mice demonstrated that deletion of Bmal1 led to the development of an asthma-like phenotype following viral infection (51). Allergic rhinitis symptoms were observed to exhibit 24-h variations with the biological clock. In particular, the Per2 gene was found to have an anti-inflammatory effect on the regulation of GATA3 and RORγt levels in the immune cells which can explain the diurnal variability of allergic rhinitis symptoms (52). IgE-mediated cutaneous reactions were also observed to show a diurnal rhythm and the Per2 gene was again found to be associated with this behaviour by controlling the secretion of glucocorticoid and gating steroid response of mast cells (53, 54). Human studies demonstrated that patients with well-controlled asthma and nocturnal symptoms had significantly lower expression of Bmal1, Ck1, Clock, Cry1/2, and Per1/3 compared to those without nocturnal symptoms (55). A study of the circadian transcriptome in simulated NSW revealed that although 73% of the transcripts continued to be expressed rhythmically and at a similar phase relative to habitual bedtimes, they did so at reduced amplitudes (32). These findings may help explain the temporality between NSW and asthma phenotype. Despite the recent associations between NSW and asthma, the mechanism by which clock genes interact at a cellular level to impact the circadian variation of asthma remains unclear. Chronotype is emerging as a crucial factor in developing personalized SW schedules to improve health. Longitudinal studies of chronotypes and related genetic polymorphism with asthma phenotypes and circadian mechanisms may help advance our understanding of chronotherapy and SW optimization.

Night shift work associated with COPD

COPD exacerbations were observed more often in the early morning or late at night, with a higher risk of hospitalization and intubation (10). The circadian variation of lung function (FEV₁) coupled with the increased vagal-induced bronchoconstriction and mucus hypersecretion has been found to exaggerate COPD symptoms (11). Extensive evidence has linked molecular clock pathways to the pathogenesis of COPD. Cigarette smoke (CS) exposure alters clock gene expression in mouse lungs by decreasing proteins BMAL1, REV-ERBα, PER2, and increasing RORα (56, 57). Deletion of Rev-erbα worsened inflammatory responses in the lung, while loss of Rorα was protective against CS-induced distal emphysematous change (58, 59). CS also decreased the rhythmic levels and activity of Sirtuin1 (SIRT1), also known as NAD-dependent deacetylase of BMAL1 and PER2 proteins, thereby enhancing BMAL1 degradation in lung tissue (56, 60). Reduced BMAL1 levels result in the upregulation of RORγt to help regulate Bmal1 transcription. RORγt, however, also promotes Th17 differentiation. As a result, patients with COPD had significantly higher levels of IL-17 was associated with worse symptoms and marked airflow limitation (23).

Although studies assessing the temporality between COPD and NSW are lacking, the detrimental effects of sleep deprivation on COPD are well documented (61–63). Sleep-deprived adults were associated with almost a five-fold higher chance of COPD exacerbation and more than 11-fold emergency visits for respiratory-related complaints. Additional evidence suggests that insomnia predicted COPD exacerbations and worse survival during follow-ups (62). Insomnia, another accompaniment of COPD, was up to 76.4% more common in NSWs compared to the general population (64). Lower sleep efficacy has also been associated with increased circadian disruptions, leading to heightened inflammatory responses (65). Melatonin and melatonin receptor agonists, Ramelteon, have been used in COPD to increase sleep efficiency and sleep duration, reduce lung oxidative stress and symptoms of dyspnea, and ultimately improve sleep quality without changing lung functions (66). Studying the role of countermeasure strategies for NSW (like phase advance shift schedules, short naps before night shifts, and bright light therapy) on COPD exacerbations can help to provide insights into disease management (67). Overall, further studies are required to assess the temporality of circadian misalignment in COPD progression and exacerbations.

Night shift work associated with pulmonary fibrosis

Recent studies suggest short and long sleep durations, late chronotypes, and SW is associated with the development of pulmonary fibrosis (PF), reiterating the pivotal role of circadian clock genes in lung pathology (12) (Table 2). While disruption of Rev-erbα in fibroblastic cells was found to promote myofibroblast differentiation, its activation inhibited TGFβ-induced fibrotic response (12). Rev-erbα expression repressed collagen deposition via the TBPL1-Integrin β1 signaling pathway, thereby preventing fibrosis. Increased Bmal1 expression and decreased Per1-3 and Rev-erbα expression in murine models were associated with increased collagen deposition in the lung tissue (68, 69). However, Bmal1 inhibition prevented myofibroblast differentiation in normal human lung fibroblasts, suggesting the gene’s pivotal role in the TGFβ1-mediated pathway and fibrogenesis (70).

The EuRhythDia study observed active NSWs having a significantly higher Rev-erbα/Bmal1 ratio than former NSWs who had stopped NSW for at least two years (71). With the current evidence, it can only be hypothesized that the increase in Rev-erbα and decrease in Bmal1 in NSW occur as a compensatory mechanism to circadian misalignment, and when the expression of these genes is altered, it can result in the manifestation of disease including PF. Longitudinal studies establish the temporality between gene expression in NSW and PF, however, this will require further testing based on conducting cross-sectional and longitudinal cohort studies. Fibroblasts have been identified as the primary cell type responsible for depositing extracellular matrix (ECM) in fibrosis. Chang et al. demonstrated that synchronized fibroblasts exhibit an autonomous and circadian function expression characterized by nocturnal pro-collagen synthesis, daytime collagen fibril assembly, and subsequent collagen degradation by the end of the circadian cycle (72).

Interestingly, Clock mutations in the fibroblasts did not impair the cell’s capacity to produce extracellular collagen; however, the cells failed to reach a homeostatic plateau and produced more collagen fibers per cell. The tendons of mice with Bmal1 deletion were significantly thicker, worse in mechanical properties, and microscopically, displayed aberrant collagen fiber distribution and architecture. The role of the circadian clock in maintaining collagen homeostasis is evident in these studies; however, preliminary findings from a recent study suggest the bidirectional dependence of these two entities (73). Garva et al. demonstrated that nearly 16% of detected proteins lost or reversed their time-dependent rhythmicity after the matrix homeostasis was disrupted using metalloproteinase-14 (MMP14) (73). Future studies providing insights into the circadian clock-collagen matrix homeostasis pathway in pulmonary fibrosis may help advance our approach to chronotherapy. NSW has been observed to result in a pro-inflammatory milieu as evidenced by high IL-6 reports in multiple cohorts of NSW. The resulting increase in IL-6 and IL-6-IL6R trans-signaling can drive chronic inflammation, activate the TGFβ pathway, and ultimately promote pulmonary fibrosis (74–78). Overall, further understanding PF pathophysiology, circadian clock-collagen homeostasis, and the impact of NSW and chronotypes on PF will help develop appropriate workplace strategies and novel clock-based therapeutics for PF.

Night shift work associated with COVID-19 infection

Recent epidemiological studies have found NSW associated with up to a three-fold higher risk of developing COVID-19 infection (79). Interestingly, irregular NSW (defined as participants working ‘sometimes’ or ‘usually’ between 0:00 am and 6:00 am) was associated with a higher risk of COVID-19 infection compared to permanent NSW. Martin et al. demonstrated similar findings where healthcare workers working nights less than weekly had higher odds of COVID-19 infection compared to those who worked nights weekly or always (80). We speculate that irregular NSW had a higher risk of developing infection compared to permanent NSW due to frequent oscillatory shifts may have significant effects on the core circadian clock gene expression (altered rhythms of circadian period, phase, and/or amplitude) and thereby enhance circadian disruption like what was observed in simulated NSW PBMC transcriptome (32). It may be interesting to study rhythms of clock gene expression and their effects over time among NSW with these two different working schedules to further explain the phenomenon. Future studies addressing the molecular mechanism behind the greater prevalence of developing COVID-19 in irregular NSW will provide additional line of evidence that supports this phenomenon. Recent studies observed similar findings of increased susceptibility to COVID-19 infection in association with NSW (81–83) (Table 2). Furthermore, NSW was associated with a two-fold increase in the risk of severe COVID-19 infection in the general population and an up to a seven-fold increase in risk for healthcare workers (84).

The circadian disruption arising from NSW can affect the innate and adaptive immune responses against viral infection. Viruses, including SARS-CoV-2, rely on host cell machinery for their replication and dissemination. With recent studies showing more than 80% of protein-encoding genes in primates are entrained by a circadian-dependent expression, it is not surprising to see host clock components directly impacting virus replication (85). The SARS-CoV-2 interacts with 332 human proteins, and nearly 30% of these host factors demonstrate circadian rhythms (86). Increased SARS-CoV-2 shedding around 2:00 pm also suggests the role of the host cell clock on viral replication (87). Adequate Bmal1 expression is required for the vesicular trafficking and synthesis of proteins necessary for SARS-CoV-2 replication (88). Bmal1 also affects mouse Herpes infection, wherein its deletion significantly enhances Herpes virus replication. Low Bmal1 expression was also found to increase viral virulence (89). Interestingly, the viral entry of SARS-CoV-2 was enhanced directly or indirectly by the abundance of Bmal1 and Clock expression in human monocytes (90).

Circadian misalignment and sleep deprivation can significantly increase tumor necrosis factorα (TNFα), interleukin 10 (IL-10), interleukin 6 (IL-6), and C-reactive protein (CRP) (91, 92). Sleep deprivation leads to decreased activity of CD56, CD16, and CD57, which are required for host immunity against viruses (93, 94). Previous influenza and hepatitis vaccination studies have demonstrated poorer vaccine efficacy following sleep deprivation (95, 96). The upcoming S-CORE study aims to provide valuable insights into the association of sleep and antibody responses to COVID-19 vaccination and vaccine efficacy in NSW (97). Zhang et al. reported that the morning administration of the SARS-CoV-2 vaccine resulted in a two-fold increase in titers of neutralizing antibodies in healthcare workers (98). Another study by Wang et al. reported better second-dose vaccine efficacy during afternoon vaccine administration (99). However, recent study demonstrated no statistical difference in antibody response and chronotypes to the time-of-day administration of the SARS-CoV-2 vaccination (100). Currently, there is limited evidence to support the timing of the SARS-CoV-2 vaccination has better efficacy. More studies are needed to ascertain whether dosing the COVID-19 vaccine at a specific time of day mediates a higher degree of protective immune response in the general population and among NSW.

Chronotherapy in chronic lung diseases

Chronotherapy is a promising therapeutic intervention wherein drug dosing is based on an individual’s circadian rhythm. This therapy has been shown to optimize drug action and lessen the possible drug-associated adverse effects. Nocturnal asthma, for example, responded favourably when parasympathomimetic drugs, like salbutamol, were administered to have a peak effect at 4:00 am when asthma-related symptoms were the worst (101). The use of long-acting beta-2 adrenergic receptor agonists, a single daily dose of bambuterol (20 mg) in the evening, and a time-dependent pulsed release system of oral salbutamol have been shown to control nocturnal asthma effectively (102, 103). The single-dose administration of 800 μg of triamcinolone at 15:00 pm was shown to produce a better response in nocturnal asthma compared to conventional therapy of 200 μg, four times a day of conventional steroid therapy (104). Chronotherapy may also have implications for COPD management. A randomized control study showed that although combination therapy of tiotropium in the morning and formoterol twice daily was most beneficial for moderate to severe COPD, the administration of tiotropium in the evening and formoterol twice daily reduced night-time symptoms of COPD. This observation also highlights the time-dependent role of tiotropium administration in managing night-time COPD symptoms (105). Novel chronotherapeutic strategies in pulmonary fibrosis targeted at the REV-ERBα and NRF2 could benefit disease management. However, evidence supporting this therapy is largely limited to animal models (12, 68) and remains to be clinically established in PF patients based on existing therapies.

Future perspectives

Circadian misalignment or circadian disruption due to SW can negatively impact health and increase the risk of developing and/or exaggerating chronic lung disease. Although longitudinal studies are limited to proving the direct causal-effect relationship between circadian disruption and chronic pulmonary disease, our current understanding of the role of circadian clock genes in lung pathophysiology warrants insights into establishing safeguards for individuals working night shifts. Establishing certain safeguards for NSW including 1) ≤ 3 consecutive night shifts 2) shift intervals of ≥ 11 hours; and 3) ≤ 9 hours shift duration, can help promote positive sleep behaviours (106). It may also be crucial to ensure adequate sleep by addressing components of shift work like the number of days off, and intensity of NSW (night shift hours/week, lifetime mean night shifts/month, and the mean number of night shifts/week) (107–110). Targeting NSW for early vaccination programs may also be beneficial. However, longitudinal studies are required to attest to this. Besides optimizing SW schedules, including chronotype assessments before work-shift allotments, may help promote health and increase workers’ productivity. Having phase advance (clockwise) schedules during changes in shifts has also been shown to be better tolerated (111).

Recent insights into chronotypes (early and late) can also help tailor work schedules by matching chronotypes to the time of work shift (morning or night), respectively (112, 113). Using light-therapy lamps and blue-light filters have shown to be beneficial in some studies, however, evidence regarding this has been inconclusive (114). Melatonin supplementation and light exposure can help shift workers adapt and shift their circadian phases during night shifts (115). There has been growing evidence of the effect of exercise on circadian phase advances and delays where treadmill exercises performed in the biological morning or biological afternoon can help advance the circadian phase. If performed in the late biological evening, the same exercise can help delay the circadian phase (116). Although these findings need to be validated through more extensive studies, they may help workers adapt their exercise routines depending on their SW. Time-restricted eating for NSWs (consuming caloric-rich food between a fixed window, i.e., 07:00 and 19:00) was associated with superior glycemic control and overnight cognitive function (117). Consumption of food or drinks during the biological night period can disrupt peripheral clocks and thus should be limited to the consumption of micronutrient-dense foods. Using digital devices such as continuous glucose monitoring systems and wearables with temperature sensors may provide information regarding optimizing the health of individuals working night shifts by providing real-time feedback. The impact of these behavioural modifications on pulmonary disease in NSW, however, has not yet been explored.

There are significant challenges in assessing the impact of circadian disruption in humans because of chronotypes and unique lifestyles. Our current understanding of biological clock machinery is primarily derived from animal models that have distinctly different sleep-wake cycles and polyphasic sleep patterns. Developing a panel of biomarkers to study human circadian biology and circadian disruption may provide valuable insight into the effect of NSW and sleep deprivation on pulmonary disease. Circulating exosomal miRNA has recently been identified to play a key role in metabolic dysfunction in NSWs, and mRNA microarrays and exosomal miRNA arrays may be a promising tool to study circadian disruption by identifying novel circulating biomarkers in the future (118, 119). Utilizing gene expression ratios like the Rev-erbα/Bmal1 ratio may provide valuable insights into other potential biomarkers for circadian clock disruption in circulating immune cell types. The population involved in NSW can help provide key insights into the effect of circadian disruption on chronic disease with a capacity to help establish temporality. This understanding can help introduce disease preventive measures in shift-based employment and direct chronotherapeutic precision medicine research.

Conclusion and future directions

NSW is a cause of circadian misalignment that can aggravate detrimental metabolic change. Identifying how specific clock genes contribute to circadian misalignment using target gene (global and cell type-specific) KO mouse models will enable us to better understand the impact of circadian disruption on lung pathophysiology. The clinical translation of this understanding in human biology remains to be explored. Currently, the UK Biobank offers the most extensive dataset for studying the impact of SW on pulmonary disease. This resource, however, does not provide insight into circadian gene expression in this population. Creating databases in collaboration with other countries with an emphasis on circadian behaviour and disease will help broaden our perspective on the potential impact of circadian disruption. Identifying and studying circadian clock genes in humans is challenging owing to the varied lifestyle and logistics behind frequent sampling and gene expression profiling, which necessitates establishing a panel of biomarkers that can help in quicker and more practical gene analysis. It is evident through the current literature that NSW can negatively impact lung function, increase both systemic as well as local inflammation (lung), and have poorer outcomes for lung diseases like asthma, COPD, and PF. Future studies designed with longitudinal prospective cohorts can further help stratify the risk associated with NSW. Using digital wearables with temperature sensors and continuous glucose monitoring systems can help study the impact of behaviour modifications in NSW, including time-restricted eating patterns. Further studies are required to study the impact of these behaviour modifications on NSW and its close association with the development of pulmonary disease. Integrating our understanding of circadian biology into medicine through behaviour optimizations and chronotherapy will help devise better preventive healthcare and precision medicine practices.

Abbreviation list

ABCA1

ATP binding cassette subfamily A member 1

ARNT

Aryl hydrocarbon receptor nuclear translocator like

BMAL1

Brain and muscle ARNT-Like 1

CAMK2D

Calcium/calmodulin dependent protein kinase II delta

CCGs

Clock-controlled genes

CLOCK

Circadian locomotor output cycles kaput

COPD

Chronic obstructive pulmonary disease

CRY

Cryptochrome

Csnk1ε

Casein kinase 1 epsilon

DBP

D-box binding protein

Dec1

Deleted in esophageal cancer 1

GHRL

Ghrelin and obestatin prepropeptide

IL

Interleukin

KCNV2

Potassium voltage-gated channel modifier subfamily V member 2

KO

Knockout

NFIL3

Nuclear Factor Interleukin 3 regulated

NK

Natural killer

NSW

Night shift work

NSWs

Night shift workers

PBMC

Peripheral blood nuclear cell

PEF

Peak expiratory flow rate

PER

Period

PF

Pulmonary fibrosis

PRDX2

Peroxiredoxin 2

ROR

Retinoic acid-related orphan receptor

RORE

ROR response elements

ROS

Reactive oxygen species

SCL3A2

Solute carrier family 3 member 2

SCN

Suprachiasmatic nucleus

Stat3

Signal transducer and activator of transcription 3

SW

Shift work

TTFL

Transcriptional-translational feedback loops