The Implications of Biological Clock on Lung Health

The body’s biological clock is interfered with by abnormal sleep habits, such as those of night shift workers, which have been connected to lung health problems.

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Researchers from the University of Rochester Medical Center (URMC) have just published a study that demonstrates how the REV-ERBα biological clock molecule affects lung scarring while also revealing new possible therapeutic targets and drugs.

Pulmonary fibrosis, also known as lung scarring, is an acute condition in which connective tissue accumulates in the lungs, thickening and rigidifying them and making breathing difficult. While drugs can alleviate pulmonary fibrosis symptoms, none can repair the lung damage produced by this potentially deadly condition.

The URMC study, which was published in Nature Communications, validates a previously observed association between the body’s biological clock (or circadian rhythm) and lung disorders while also revealing a novel mechanism underpinning this link.

The researchers discovered that a deficiency of the circadian rhythm protein, REV-ERBα, causes lung scarring in mice by boosting the synthesis of collagen, a main component of connective tissue, and lysyl oxidase, which stabilizes and stiffens connective tissue.

The study, led by Irfan Rahman, Ph.D., Dean’s Professor of Environmental Medicine at URMC, discovered low levels of REV-ERB and high levels of collagen and lysyl oxidase in lung samples from individuals with pulmonary fibrosis. Inducing lung damage in mice showed a similar result: lower REV-ERBα levels and higher levels of collagen, lysyl oxidase, and other fibrosis markers.

REV-ERBα expression swings throughout the day as a circadian rhythm protein, peaking at midday and dropping to its lowest levels at midnight. When the researchers caused lung injury at night, they found that mice had higher levels of lysyl oxidase and collagen proteins, more severe lung damage, and worse survival rates than mice injured in the morning.

This, according to Rahman, could be significant to night-shift workers who are exposed to lung irritants during work.

Night-shift work usually occurs during the midnight timeframe when the expression of REV-ERBα is lowest. Our study suggests there is less protection against lung fibrosis generated from REV-ERBα activation at night.

Irfan Rahman, Ph.D., Dean’s Professor, Environmental Medicine, University of Rochester Medical Center

When the researchers caused lung damage in genetically modified mice with low levels of REV-ERBα, the mice had worse outcomes, which appeared to be mediated by increased collagen and lysyl oxidase.

After 15 days of influenza A infection, these mice had higher amounts of collagen and lysyl oxidase gene expression, worse flu infections, and worse lung damage than mice that expressed normal levels of REV-ERBα.

In mice that express normal levels of REV-ERBα, activating REV-ERBα with a drug 14 days after lung damage marginally lowered collagen and lysyl oxidase gene expression and improved lung health. The REV-ERBα-activating drugs demonstrated an anti-fibrotic effect when evaluated in cell cultures.

Currently, there are only two drugs approved by the FDA to treat fibrosis, and they only delay the process, they don’t cure the disease. REV-ERBα-activating drugs could serve as potential therapeutics to help prevent fibrosis and stop the disease process.

Qixin Wang, Ph.D., Study Author and Postdoctoral Fellow, University of Rochester Medical Center

He also stated that a better REV-ERBα drug or a more direct method of delivering the drug is required. In their study, mice administered with the REV-ERBα activating drug SR9009 lost more weight and lived shorter than untreated mice.

While further study is needed, Rahman and Wang believe their findings offer up new avenues for creating therapies for fibrotic diseases in general, particularly those with a circadian component, such as nocturnal alcohol intake causing liver fibrosis.

Source:
Journal reference:

Wang, Q., et al. (2023). Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization. Nature Communications. doi.org/10.1038/s41467-023-36896-0

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