A study has found that abnormal sleep patterns disrupt the body’s natural biological clock and are linked to lung health problems. The study was published in the journal ‘Nature Communications’. Researchers are now exploring how a biological clock molecule, called REV-ERBA, contributes to lung scarring, helping uncover new potential drugs and drug targets along the way.
Pulmonary fibrosis, or scarring of the lung, is a serious condition in which connective tissue builds up in the lungs, making them thick and hard, and making breathing difficult. While medications can ease the symptoms of pulmonary fibrosis, none can reverse the lung damage caused by this sometimes-fatal disease.
This confirms a previously discovered link between the body’s biological clock (or circadian rhythm) and lung diseases and uncovers new mechanisms underlying this link. Study authors show that deficiency of the circadian rhythm protein, REV-ERBA, contributes to lung scarring in mice by increasing the production of collagen, a major component of connective tissue, and lysyl oxidase, which stabilizes connective tissue and makes it more rigid.
A team led by Irfan Rahman, PhD, dean professor of environmental medicine at URMC, found lower levels of REV-ERBA and greater amounts of collagen and lysyl oxidase in lung samples from patients with pulmonary fibrosis. Inducing lung injury in mice had a similar result: a decrease in REV-ERBA levels and an increase in collagen levels, lysyl oxidase, and other markers of fibrosis.
As a circadian rhythm protein, REV-ERBA expression typically fluctuates throughout the day, peaking at midday and sinking to its lowest level at midnight. When the team injured the lungs at night, the mice had greater increases in lysyl oxidase and collagen protein, greater lung damage, and lower survival rates than mice injured in the morning.
Rahman said this could be relevant for night-shift workers exposed to lung irritation on the job. “Night-shift work usually occurs around midnight when expression of REV-ERBA is lowest,” he said. “Our study suggests that there is less protection against lung fibrosis induced by REV-ERBA activation at night.”
When the team induced lung injury in genetically modified mice that express low levels of REV-ERBA, the mice had worse outcomes that appeared to be mediated by increased collagen and lysyl oxidase. 15 days after infection with influenza A, these mice had higher upregulation of collagen and lysyl oxidase gene expression, worse flu infection, and worse lung injury than mice expressing normal levels of REV-ERBA.
Activation of REV-ERBA with drugs 14 days after lung injury in mice led to normal levels of REV-ERBA, slightly reduced collagen and lysyl oxidase gene expression and improved lung health in mice, although not significantly. When tested in cell cultures, REV-ERBA-activating drugs had an anti-fibrotic effect.
“Currently, there are only two drugs approved by the FDA to treat fibrosis, and they delay the process, they don’t cure the disease,” said study author Qixin Wang, PhD, a postdoctoral fellow in Rahman’s lab. . “REV-ERBA-activating drugs may serve as potential therapies to prevent fibrosis and help slow the disease process.”
But, he adds, a better REV-ERBA drug or a more direct way to deliver the drug is needed. In their study, mice treated with the REV-ERBA-activating drug SR9009 lost more weight and lived shorter than untreated mice.
While more research is needed, Rahman and Wang believe their findings open up new possibilities for developing treatments for all types of fibrotic diseases — especially those with a circadian component, such as the nighttime alcohol consumption causes liver fibrosis.
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