The build-up of abnormally thick mucus and the associated inflammation appear to be the initiating cause of damage to the lungs of children with cystic fibrosis (CF), rather than bacterial infections, according to a UNC School of Medicine study published in Science Translational Medicine.
The research suggests that doctors might be able to delay the onset of lung disease in young children born with CF, and possibly allow them to live significantly longer. The key would be to use early treatments that thin out mucus.
“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,” said co-first author Charles R. Esther, Jr., MD, PhD, professor of pediatrics at the UNC School of Medicine and member of the UNC Marsico Lung Institute.
Esther, co-first author Marianne Muhlebach, MD, professor of pediatrics at the UNC School of Medicine, and a multidisciplinary group of researchers at UNC-Chapel Hill—collaborating with Australian researchers led by Dr. Stephen Stick—looked not at animal models but at CF patients themselves. The researchers analyzed the contents of “lavage” fluid that had been used to rinse the lungs of 46 young children with CF as part of an Australian clinical study and compared the samples to lavage fluid from 16 other Australian children with asthma and other non-CF airway ailments.
Bacterial infection has been suspected as an early driver of lung damage in CF, but the researchers found little evidence of bacteria in the young CF patients’ lavage fluids. In fact, they found more bacteria on average in the non-CF samples.
Here’s the key difference: the CF samples contained more evidence of mucus, implying that CF causes patients to produce or accumulate more of it. Also, the CF mucus was much more likely to be a more solid “flake” form with a high concentration of proteins called mucins. And here’s another important finding: areas of the CF lungs where serious damage had not yet occurred still featured an abnormally high concentration of mucins and signs of inflammation, even without strong evidence of infection.
Researchers now hypothesize that in young CF patients, mucus that is secreted—as it should be during ordinary viral respiratory infections—isn’t fully cleared because it is abnormally thick. It builds up in the airway and creates a low-oxygen condition in airway-lining cells. This triggers inflammation, which stimulates more mucus secretion and more inflammation.
This “positive feedback loop” ultimately results in scarring and progressive loss of lung function. Recurrent infections with dangerous bacteria begin at some point during this process and worsen the disease course. But those infections, the researchers say, are likely not the earliest drivers of lung damage.
The finding that lung inflammation in CF children appears to result initially from thick airway mucus, not bacterial infection, suggests that early mucus-thinning interventions might delay the course of the disease.
