Scientists at the University of North Carolina (UNC) School of Medicine developed a model of cystic fibrosis (CF) that may help to test current and future CF therapies.
This model, showing how airway cells respond to environmental factors, also brought new insights into the thick mucus observed in CF patients.
CF is a genetic disease characterized by muco-obstructive airways caused by a defective or absent cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR-mediated fluid secretion keeps mucus hydrated, which is critical to capture and flush inhaled bacteria and viruses from the lungs.
An abnormal or absent CFTR protein leads to airway surface dehydration, causing a buildup of thick and sticky mucus, in which inhaled pathogens can thrive. The resulting chronic inflammation and infection cause progressive lung damage and scarring (fibrosis).
The mechanisms behind the characteristically thick and sticky mucus in CF patients are still not well understood. However, impaired mucus transport — derived from altered mucin production — is believed to be one of the causes. Mucins are the major components of airway mucus and are necessary to move mucus through the airways. The relative rates of mucin vs. liquid secretion determine the hydration status of airway mucus.
Researchers at UNC investigated these responses in CF. They developed a CF model with elements taken from CF patients during lung transplants: airway cells (bronchial epithelial cells) and a mix of infectious and inflammatory factors present in their airways. This factor mix represents the inflammatory stress associated with chronic infection in CF.
“This model is important because it contains the mix of infectious/inflammatory factors in the airways of CF patients,” Carla Ribeiro, the study’s principal investigator, said in a press release. “Understanding how airway cells respond to that environment gives us a better way to assess pre-clinically the likely effectiveness of novel CF therapies.”
Mucin production and fluid secretion were assessed in vitro in normal and in CF airway cells exposed to the CF-related infectious and inflammatory factors.
Chronic (long-term) exposure to these factors was found to promote similar levels of mucin secretion and accumulation in healthy and CF cells.
“Our results show that the CF mucin response to infectious/inflammatory factors is really the same as that of normal airway cells” said Lubna Abdullah, the study’s first author.
However, CFTR-mediated fluid secretory response was found to be impaired in CF cells compared to normal cells. The absence of fluid secretion in CF cells increased the dehydration of the mucus.
“We showed unequivocally with this model that the lack of CFTR function in the CF airway cells leads directly to the dehydrated mucus seen in the disease,” Ribeiro said.
The team is now working with pharmaceutical companies to use the model to test prospective CF drugs. Researchers believe their findings might also be relevant to non-CF bronchiectasis (NCFB), an obstructive disease milder than CF.