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Mucus and Inflammation, Rather Than Infections, are Early Drivers of Lung Disease in CF, Study Says

Early accumulation of abnormally thick mucus and inflammation in the lungs, rather than bacterial infections, may be the initial trigger of lung disease during cystic fibrosis (CF), a new study suggests.

Bacterial infections have been thought of as an early driver of CF disease, but mucus build-up and inflammation of the airways is already evident early in children with CF, despite little or no signs of infection.

The results suggest that timely treatment of CF children with mucolytics — agents that help dissolve the mucus and make it more fluid — and anti-inflammatory therapies may delay the onset of lung disease and worse CF symptoms, potentially improving their life expectancy.

“How lung disease starts in the youngest kids with CF hasn’t been well understood, but with this study we can see what processes come first and develop strategies to target them to help patients,” Charles R. Esther, Jr., MD, PhD, a specialist in pediatric pulmonology and one of the leading authors of the study, said in a University of North Carolina (UNC) news story.

Esther is also a professor at the UNC School of Medicine and member of the UNC Marsico Lung Institute.

Together with Marianne Muhlebach, MD, professor of pediatrics at the UNC School of Medicine, colleagues from UNC-Chapel Hill, and collaborators from The University of Western Australia, the team joined efforts to understand the first stages of CF disease development.

Researchers analyzed the contents of bronchoalveolar lavage fluid (BALF) of 46 children with CF, younger than 6, enrolled at an early surveillance program in Australia, AREST CF; another 16 children with asthma and other non-CF airway disorders were used as controls.

BALF is a “lavage” fluid used to rinse the lungs and collected for examination. It is commonly used to study the immune system cells, infectious agents, or other molecules present in the airways, and to diagnose lung problems.

Results showed that abnormal mucus build-up was evident in CF BALF, associated with a higher concentration of inflammatory markers and proteins called mucins. Mucins are a group of proteins attached to sugars, key for giving mucus a gel-like texture, that serve to lubricate and create a protective barrier.

An important finding was that these changes apparently did not depend on bacterial infections as there was little, if any, evidence of bacteria in the young patients’ fluids.

In fact, on average there were more bacteria potentially harmful in the non-CF samples.

The data suggests that it is actually the early accumulation of mucus and inflammation, and not the occurrence of bacterial infections, that leads to serious lung injury and disease.

Another finding supported this idea. BALF samples from CF patients were particularly rich in mucus flakes difficult to dissolve, as if they were permanent gels, most likely due to its high content of mucins.

Also children without serious lung damage, unremarkable on CT scans, had an increased density of mucus flakes and white blood cells associated with inflammation (neutrophils).

In light of these findings, the team proposed that infections caused by common respiratory virus or aspiration (when food and liquids are inadvertently breathed into the lungs) trigger mucus secretion. But due to its high thickness, the mucus would not be completely completely cleared. This deprives tissues from oxygen, inducing more inflammation; in turn, that also stimulates the production of additional mucus and inflammatory responses.

This vicious cycle can continue until the lungs eventually get scarred and progressively lose their function. Recurrent infections can break in at some point during this process, but are not its leading drivers.

These findings suggest that early treatment with mucus-thinning or anti-inflammatory agents might be explored as a preventive treatment, to delay the course of the disease. Therefore, in a pilot test, researchers tested several mucus-thinning compounds on the mucin flakes collected from the CF BALF samples.

They saw that two FDA-approved compounds that are used in CF — DNase, the active ingredient of Pulmozyme, and N-acetylcysteine (NAC) — failed to dissolve the flakes.

But an investigational compound called P2062 seemed to work. This compound has not been tested yet in people and is under development by UNC researchers and Parion Sciences.

“We are now trying to find new therapeutic agents that could help remove these flakes in CF patients,” Esther said.

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