A new study shows how a circadian clock molecule contributes to lung scarring and what could help cure pulmonary fibrosis caused by night-time alcohol consumption.

Pulmonary fibrosis, a condition characterized by the accumulation of connective tissue in the lungs, results in thickening and rigidity of the lungs, leading to breathing difficulties. Although medications can alleviate the symptoms associated with pulmonary fibrosis, none can restore the lung damage that often accompanies this life-threatening disease.

Biological clock impact on lung health

Disturbances in the body’s natural circadian rhythm caused by irregular sleep patterns, such as those experienced by night-shift workers, have been associated with respiratory problems.

Researchers from the University of Rochester Medical Center (URMC) have revealed how REV-ERBα, a biological clock molecule, plays a role in the development of lung scarring, opening up new avenues for potential drugs and drug targets.

Published in Nature Communications, the study conducted by URMC affirms the pre-existing correlation between the body’s circadian rhythm and lung diseases while exposing a novel mechanism that underpins this connection.

The authors of the study demonstrate that insufficient levels of the circadian rhythm protein, REV-ERBα, elevate the production of collagen and lysyl oxidase, both of which are integral to connective tissue. This contributes to lung scarring in mice by making the tissue more rigid and inflexible.

Lung scarring mechanism

Led by Irfan Rahman, PhD, the Dean’s Professor of Environmental Medicine at URMC, the research team discovered diminished levels of REV-ERBα alongside elevated amounts of collagen and lysyl oxidase in samples obtained from patients with pulmonary fibrosis. The findings were mirrored in mice that had sustained lung injuries, as the experiment resulted in a decline in REV-ERBα levels accompanied by an increase in collagen, lysyl oxidase, and additional markers associated with fibrosis.

REV-ERBα, being a circadian rhythm protein, experiences regular fluctuations throughout the day, with its peak expression being observed at noon and the lowest levels at midnight. The research team noticed that when mice were inflicted with lung injury at night, there was a greater surge in the production of lysyl oxidase and collagen proteins, resulting in more severe lung damage and reduced survival rates, as compared to the mice who had incurred injury in the morning.

According to Rahman, these observations could have implications for night-shift workers who are exposed to lung irritants during their work hours.

“Night-shift work usually occurs during the midnight timeframe when the expression of REV-ERBα is lowest,” he adds.

These findings suggest “there is less protection against lung fibrosis generated from REV-ERBα activation at night.”

The research team conducted experiments on genetically modified mice with reduced levels of REV-ERBα, wherein they induced lung injury. The results showed that the mice with low levels of the circadian rhythm protein had a more unfavorable outcome due to heightened production of collagen and lysyl oxidase.

Subsequently, after 15 days of infection with influenza A, these mice exhibited a more pronounced upregulation of genes associated with collagen and lysyl oxidase, more severe flu infections, and worse lung damage as compared to mice with normal levels of REV-ERBα.

REV-ERBα: The Circadian Rhythm Protein that Could Help Prevent Fibrosis

Administration of a drug that activates REV-ERBα, 14 days post lung injury in mice with normal levels of the circadian rhythm protein, resulted in a minor decrease in the expression of genes related to collagen and lysyl oxidase, and a slight improvement in lung health. However, the findings were not statistically significant. Upon examination in cell cultures, the REV-ERBα-activating drugs demonstrated an anti-fibrotic effect.

According to Qixin Wang, Ph.D., a postdoctoral fellow who worked on the study in Rahman’s laboratory, there are only two FDA-approved drugs available for treating fibrosis, and they only offer a delay in the progression of the disease and not a cure.

Wang believes that drugs that activate REV-ERBα have the potential to act as therapeutics, which can help prevent fibrosis and halt the progression of the disease.

However, Wang emphasized the requirement for a more efficient REV-ERBα drug or a direct method for its delivery. The researchers observed that mice treated with the REV-ERBα-activating drug SR9009 lost weight and had a lower survival rate than the untreated mice.

Despite the need for further research, Rahman and Wang are optimistic that their study’s findings create new avenues for developing treatments for fibrotic diseases, particularly those with a circadian element such as liver fibrosis caused by nighttime alcohol consumption.

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