Minimal, Extended Sleep Duration Linked to Development of Pulmonary Fibrosis

People who regularly sleep less than 4 hours or more than 11 hours were found to be 2 to 3 times more likely to have pulmonary fibrosis compared with those who sleep for 7 hours a day, according to study results published in PNAS.

The circadian clock in the lung has been shown to drive critical physiological responses, including temporal gating of numerous inflammatory and antioxidant responses. When the circadian clock gene, REVERBα, is disrupted, exaggerated pulmonary responses to a model of pulmonary fibrosis has been shown to occur due to the impairment of circadian pulmonary oscillations. These disruptions can be caused by environmental disruptions such as shift work schedules or genetic deletion of core clock components, contributing to inflammatory and metabolic phenotypes.

While pulmonary inflammatory responses lie under circadian control, analyses on the importance of circadian mechanisms in the underlying fibrotic phenotype are not well documented. Researchers sought to evaluate the link of the circadian gene REVERBα to pulmonary fibrosis by analyzing the lung, whose responses to environmental insults are regulated and shaped by the circadian clock:

• Researchers analyzed the lung fibrosis within mice, including analyses conducted ex vivo and in vitro, and within human data found in the UK Biobank (n = 500,074)
• Ex vivo analysis included characterization of primary fibroblasts explanted from REVERBα under Pdgfrb control
• Precision-cut lung slices from transgenic mPER2: LUC mice were used to track circadian oscillations in real time after bleomycin induction of fibrosis

Disruption of the REVERBα gene can be caused by deletion of its DNA-binding domain, with small molecular ligands shown to modulate activity as well. When deleting the REVERBα gene, researchers found that mice experienced an exaggerated fibrotic response and increased accumulation of αSMA-positive myofibroblasts, which are known to secrete collagen, resulting in abnormal lung function, in response to bleomycin.

Ex vivo analyses found that these markers of myofibroblast activation indicated a fibroblast-intrinsic change driven by disruption of REVERBα, with culture on hard plastic providing the environmental trigger for initiation of the myofibroblast differentiation program.

For analyses occurring in the UK Biobank, researchers found that short or long sleep duration (<7 hours or >7 hours) were associated with pulmonary fibrosis, with factors such as shift work (odds ratio [OR], 1.353; 95% CI, 1.069-1.710) and evening chronotype (OR, 1.040; 95% CI, 1.001-1.080) shown as significant factors. In comparison to people sleeping 7 hours a day, those reporting regular sleep intervals of 4 hours or less in a day doubled their chance of developing pulmonary fibrosis, with those sleeping 11 or more hours per day tripling their chance as well.

Lead study author John Blaikley, MD, MBBS, senior lecturer at the University of Manchester, described how the discovery of the body clock as a potential link to pulmonary fibrosis can lead to innovative ways to treat or prevent the condition, but noted that further research is needed to confirm both causation and reproducibility of results.

“If these results are confirmed, then sleeping for the optimal time may reduce the impact of this devastating disease,” said Blaikley.

Reference

Cunningham PS, Meijer P, Nazgiewicz A, et al. The circadian clock protein REVERBα inhibits pulmonary fibrosis development [published online December 26, 2019]. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1912109117.