A new test to measure the effectiveness of CF drugs

November 16, 2017 by Mark Derewicz, University of North Carolina at Chapel Hill School of Medicine

UNC School of Medicine researchers have developed a new laboratory model of the infection- and inflammation-plagued airways of cystic fibrosis (CF) patients. The model, described in the American Journal of Respiratory and Critical Care Medicine, includes primary bronchial epithelial cells from CF patients as well as infectious/inflammatory factors normally found in the CF airways. Pharmaceutical companies are now using the new model to test existing and potential CF therapies.

In their study, the UNC scientists showed how the can be used to measure and compare the responses of CF and normal airway cells to CF-related infectious/inflammatory factors.

"This model is important because it contains the mix of infectious/inflammatory factors in the airways of CF patients," said principal investigator Carla M. P. Ribeiro, PhD, associate professor in the department of medicine and member of the UNC Marsico Lung Institute. "Understanding how airway cells respond to that environment gives us a better way to assess pre-clinically the likely effectiveness of novel CF therapies."

CF afflicts about 30,000 people in the United States, and is caused by inherited mutations in both copies of the gene that encodes the protein CFTR (cystic fibrosis transmembrane conductance regulator). In airway-lining cells, the protein controls the flow of chloride and water molecules between these cells and the thin layer of watery mucus that normally floats above them. That layer of mucus is supposed to carry inhaled bacteria and viruses out of the airways. But in CF, mucus is thick, sticky, and immobile, giving inhaled pathogens an environment in which they can thrive. The resulting chronic infections cause progressive lung damage, leading to respiratory failure. Treatments for CF include antibiotics, anti-inflammatory and mucus-thinning drugs, and even lung transplants, but most patients die before age 50.

Scientists have developed useful models of CF by engineering mice and other lab animals to have CFTR gene defects. However, to screen libraries of potential drug compounds to find any that work against CF, scientists typically need lab-dish (in vitro) models. The new in vitro model developed by Ribeiro and colleagues uses bronchial epithelial cells and mucopurulent materials from lungs that were removed from CF patients during lung transplants. The cells are exposed to a solution derived from the CF mucopurulent material, which contains bacterial factors and inflammatory factors secreted by airway epithelia and inflammatory cells that accumulate in CF lungs with frequent infections.

UNC research associate Lubna Abdullah, PhD, the first author of the study and Marsico member, found that long-term exposure to the infectious/inflammatory factors causes both CF and normal airway cells to boost their production of proteins known as mucins, the key gel-forming components of mucus.

Some previous research had suggested that CF airway cells, compared to healthy airway cells, overproduce or even underproduce mucins. However, Ribeiro said, "Our results show that the CF mucin response to infectious/inflammatory factors is really the same as that of normal airway cells."

The big difference in the cells' responses has to do with fluid secretion: The normal cells secrete more fluid to keep the increased mucus thin and mobile, whereas the CF cells secrete hardly any fluid.

"We showed unequivocally with this model that the lack of CFTR function in the CF leads directly to the dehydrated mucus seen in the disease," Ribeiro said.

She is now working with pharma companies to use the model to test prospective CF drugs. "This model has been very useful so far in our research, and I hope it will soon be useful more broadly for the CF research community," she said.

Explore further: The mechanism of mucus: Discovery could lead to better cystic fibrosis treatments

Related Stories

The mechanism of mucus: Discovery could lead to better cystic fibrosis treatments

March 23, 2017
People with cystic fibrosis (CF) suffer repeated lung infections because their airway mucus is too thick and sticky to keep bacteria, viruses, and other pathogens from causing chronic infection. How mucus becomes abnormal ...

Cystic fibrosis alters the structure of mucus in airways

June 28, 2017
Mucus is important for maintaining healthy lungs. Inhaled particles, including bacteria and viruses, get trapped in mucus and then cilia—tiny hair like projections on the surface of the airway cells—sweep the mucus out ...

Cystic fibrosis scientists discover abnormal response to lung infections

October 6, 2017
"For a very long time, there has been discussion about whether cystic fibrosis was a bacteria-infection problem, an inflammation problem, or an immune system problem," said Juan Ianowski, the lead author of the paper published ...

Researchers further illuminate pathway for treatment of cystic fibrosis

January 13, 2016
It is well established that people with cystic fibrosis (CF) have two faulty copies of the CFTR gene, but debate continues on the question of whether certain symptoms of the airway disease are caused by the mutation or if ...

Scientists find gene linked to heightened mucus levels in lung disease

October 5, 2017
What if researchers could make breathing easier by changing how much mucus is in your lungs? Although healthy individuals have mucus in their lungs, mucus can be a major problem for people with chronic airway conditions, ...

Improved airway-targeted gene delivery in a pig model of cystic fibrosis

September 8, 2016
Cystic fibrosis (CF) is characterized by accumulation of thick mucus in the lungs and is associated with a high incidence of bacterial infection. Mutations in the gene encoding CF transmembrane conductance regulator (CFTR) ...

Recommended for you

New compound shown to be as effective as FDA-approved drugs against life-threatening infections

June 15, 2018
Purdue University researchers have identified  a new compound that in preliminary testing has shown itself to be as effective as antibiotics approved by the Food and Drug Administration to treat life-threatening infections ...

Foods combining fats and carbohydrates more rewarding than foods with just fats or carbs

June 14, 2018
Researchers show that the reward center of the brain values foods high in both fat and carbohydrates—i.e., many processed foods—more than foods containing only fat or only carbs. A study of 206 adults, to appear June ...

3-D imaging and computer modeling capture breast duct development

June 14, 2018
Working with hundreds of time-lapse videos of mouse tissue, a team of biologists joined up with civil engineers to create what is believed to be the first 3-D computer model to show precisely how the tiny tubes that funnel ...

Beating cancer at its own game with a Trojan horse telomerase

June 13, 2018
Telomerase is a reverse transcriptase that uses an RNA template to synthesize telomeres. These repeat sequences bind special proteins that fold the ends of chromosomes back onto themselves to create a stable cap. When this ...

Turning the tables on the cholera pathogen

June 13, 2018
Recent cholera outbreaks in regions that are ravaged by war, struck by natural disasters, or simply lack basic sanitation, such as Yemen or Haiti, are making the development of new and more effective interventions a near-term ...

Troves from a search for new biomarkers: blood-borne RNA

June 12, 2018
It's the critical first step in treating everything from strokes to cancer: a timely and accurate diagnosis. Today, doctors often rely on biomarkers, such as cardiac troponin, the protein that appears in the blood after a ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.