The health effects of disordered sleep patterns continue to mount. Excessively short or long sleep may increase the risk of developing pulmonary fibrosis due to disruptions to the circadian clock.
The circadian clock
The circadian clock operates as an internal body clock that regulates nearly every cell in the human body. Circadian rhythms drive changes in physiology and behavior along 24-hour cycles, a notable example being the timing of sleep and wakefulness. At a cellular and molecular level, processes such as hormone secretion and metabolism also follow a circadian clock.
The lung is a circadian organ that responds to the internal clock. Bronchial epithelial cells that line the airways are known to demonstrate a circadian rhythm, whereas cells that make up the tiny air sacks of the lungs (alveoli) have weak circadian properties. New research published in the Proceedings of the National Academy of Sciences shows that people with pulmonary fibrosis may have elevated clock oscillations in the alveolar cells, which may play a role in the etiology of this disease. The study was based out of the Universities of Manchester, Oxford, Newcastle, University College London, and Toronto and funded by the Manchester University NHS Foundation Trust.
Lung fibrosis and disorder sleep patterns
Pulmonary (lung) fibrosis is an incurable respiratory disease that involves scarring of the lung tissue and loss of proper lung function. Many cell types contribute to the development of pulmonary fibrosis. A key feature is the recruitment of fibroblasts that secrete collagen in excess, causing the thickening and stiffening of lung tissue.
Animal experiments in mice revealed that the modification of the core circadian signals could impact the fibrotic process in the lung, making the mice more susceptible to developing pulmonary fibrosis. Namely, the researchers manipulated the function of an essential circadian clock protein, REVERBα. Genetically engineered mice that lacked REVERBα protein had greater lung fibrosis, suggesting that this key circadian factor mediates fibroblast activation in vivo. The reverse effect was observed in primary human lung fibroblasts treated with a common REVERBα ligand. Pharmacological targeting using a synthetic activator compound was able to repress collagen secretion in cultured fibroblasts obtained from patients with lung fibrosis.
The researchers then used human data from the UK Biobank to show that the risk of pulmonary fibrosis is linked to several important circadian risk factors. People who regularly sleep less than four hours or over 11 hours a day were 2 to 3 times more likely than those who sleep seven hours a day to have this disease. In addition to sleep duration, other risk factors for pulmonary fibrosis included chronotype (the tendency to stay up late at night) and shift work.
Dr. John Blaikley and Dr. Peter Cunningham from the University of Manchester served as co-authors on this paper supporting the negative health effects of disordered sleep patterns. According to Blaikley, “The discovery that the body clock is potentially a key player [in pulmonary fibrosis] potentially opens new ways to treat or prevent the condition. More work will need to be done around studying the association between pulmonary fibrosis and sleep duration to establish both causation and reproducibility. If these results are confirmed, then sleeping for the optimal time may reduce the impact of this devastating disease.”
Cunningham commented on the therapeutic implications of their findings: “It is fascinating to think that clock activity is increased in fibrotic disease. Previous studies have shown that the circadian clock also plays an important role in infection, cancer, and diabetes. The discovery that the clock plays a role in fibrosis suggests that altering these oscillations could become an important therapeutic approach.”
- Cunningham PS, Meijer P, Nazgiewicz A, et al. The circadian clock protein REVERBα inhibits pulmonary fibrosis development. Proc Natl Acad Sci U S A. 2020;117(2):1139-1147. doi:10.1073/pnas.1912109117
- Addelman, M. Short or long sleep associated with Pulmonary Fibrosis. EurekAlert! (2019). https://www.eurekalert.org/news-releases/841651