NEWS

By DAVID WILLIAMSON
UNC News Services

CHAPEL HILL -- University of North Carolina at Chapel Hill scientists believe they have conclusively identified the central problem that causes cystic fibrosis lung disease, the most common lethal genetic illness among whites in the United States.

Special genetically engineered mice the researchers created revealed that cells lining patients’ airways can’t produce enough surface water and aren’t wet enough, they say. As a result, airway surfaces can’t generate a mucus coating sufficiently moist to clear unrelated but disease-causing bacteria and other inhaled contaminants from the lungs.

The new mouse model, in which sodium and water absorption are increased in the airways, promises to be the best animal model yet for studying cystic fibrosis lung disease, which strikes roughly one in every 2,000 to 3,000 infants born in the United States, the scientists say.

A report on the research will appear in the May issue of Nature Medicine. Authors are Drs. Marcus Mall, assistant professor; Barbara R. Grubb, research associate professor; Wanda K. O’Neal, research assistant professor; and Richard C. Boucher, Kenan professor, all in the UNC School of Medicine’s department of medicine.

Boucher directs the UNC Cystic Fibrosis/Pulmonary Research and Treatment Center. Dr. Jack R. Harkema, professor of veterinary medicine at Michigan State University, contributed to the work.

"With cystic fibrosis, a longstanding debate has occurred over how you go from a defective gene to the disease itself," Boucher said. "There have been a number of intriguing theories, but we think we have established that the lack of water is the fundamental defect."

The physician compared not having enough water on airway surface to those long plastic sheets children slide on at the beach. When the sheets aren’t wet enough, the children can’t slide well because of excessive traction. Likewise, airway secretions get bogged down on excessively dry lung surfaces. Then contaminants get trapped in the lungs and increasingly damage them over time.

"It has been unclear how the gene associated with cystic fibrosis, CFTR, which acts as a chloride channel and a regulator of the sodium channel, causes lung disease," Mall said. "In particular, the relative importance of these two functions has been controversial and difficult to test. This mouse model demonstrated for the first time that accelerated transport of sodium ions alone is sufficient to cause this disease link through dehydration."

Earlier work with genetically engineered mice, including some at UNC, had shown that neither malfunctioning cilia -- the tiny airway hairs that beat in unison to clear mucus -- nor over-secretion of mucus was enough to cause severe airway obstruction, Boucher said. Those findings bolster the UNC scientists’ conclusion about the disease mechanism because those mice survive, while the new ones, with only the hydration deficiency, grow increasingly sick from lung disease and die.

Mall said that since airway surface dehydration is now known to be critical in starting CF lung disease, he and others will work on developing and testing drugs that act on that root cause and improve hydration by blocking sodium channels or by increasing secretion of salt and water.

He agreed with Boucher that the new mouse model will be an extremely useful tool for future research. It also could boost investigations into smokers’ chronic bronchitis and some forms of asthma.

"We will use this model for studying factors that ultimately lead to chronic bacterial lung infections, which remain one of the biggest problems for cystic fibrosis patients," Mall said. "We also have planned studies to search for modifier genes that modulate the severity of CF lung disease and may have an impact on the severity of other chronic bronchitic airway diseases in humans."

Third, he said, the mouse will allow the scientists to investigate other environmental factors contributing to the complex progression of disease once it starts.

UNC is renowned for its basic and clinical research on cystic fibrosis. Among the center’s previous contributions has been developing the first animal model for studying the illness. Its scientists also determined that the defective cystic fibrosis gene did not die out among humans over thousands of years because -- when inherited from only one parent -- it helped protect people from cholera.

They also developed the most effective treatment so far and have been pioneers in gene therapy for the disease. UNC medical graduate Francis Collins, now director of the National Human Gene Research Institute at the National Institutes of Health, discovered the CFTR gene.

- 30 -

Note: Boucher and Mall can be reached at (919) 966-1077 or rboucher@med.unc.edu and mmall@med.unc.edu, respectively.

Media contact: David Williamson, (919) 962-8596