July 20, 2001 CHAPEL HILL – Since 1989, scientists have known which gene causes cystic fibrosis, the leading fatal genetic illness among whites in the United States, but they’ve continued to disagree over how it works. Debate has focused on questions such as how abnormalities in what’s called the CFTR gene produce lung injury. Is there too much salt in patients’ lungs, or is it that too little salt leads to stuffed-up airways and a series of chronic, debilitating infections? The right answer remains critical for determining effective treatments to restore the natural, necessary balance of salt and water, doctors say, and for avoiding therapy that would make lung damage more severe.
University of North Carolina at Chapel Hill School of Medicine researchers believe they have finally solved a key part of the long-standing puzzle.
“The answer pretty unequivocally is that there’s too little salt,” said Dr. Richard C. Boucher, Kenan professor of medicine at UNC. “This work presents a clear road map showing which fork we need to take to develop better treatments for CF lung disease. What remains is largely an engineering problem.”
A report on the research appears in the July 20 issue of Molecular Cell, a major scientific journal. Besides Boucher, authors are Drs. Robert Tarran, Maryse Picher and Andrew J. Hirsh, research associates; Barbara Grubb, associate professor of medicine; and C. William Davis, research associate professor of cell and molecular physiology, all at UNC. David Parsons of Women’s and Children’s Hospital in Adelaide, Australia, contributed to the work.
Boucher directs UNC’s Cystic Fibrosis/Pulmonary Research and Treatment Center. He said part of the reason the contentious salt controversy had not been resolved was because the layer of salt and water that coats airways in the lung is only about a millionth of an inch thick. As a result, it has been extremely difficult to study. Also, directly working on babies’ lungs was out of the question for ethical and practical reasons.
“We studied mice genetically engineered here at UNC several years ago to serve as an animal model for cystic fibrosis,” the physician said. “Cells lining the nose of the CF mouse have the same problem with salt transport that cells lining the lungs of CF patients do, and this problem can be measured electrically with a device similar to an electrocardiograph machine.
“The question was whether the abnormal electrical activity was associated with disease in the mouse, and it was,” Boucher said. “The mouse exhibited the same kind of airway disease as human CF patients. They had a lot more mucus-secreting, infection-fighting cells, called goblet cells, than they would have normally. The question then became what was the link between abnormal electrical activity and diseased airways – too little salt or too much salt? The answer was too little salt.”
Next the group experimented with cultured human airway cells from CF patients and found several possible ways of restoring the salt balance to prevent injury, he said.
“The models we used were very good because they actually showed that if you add a certain amount of salt back, you’ll promote clearance of this sticky mucus, which is the problem in cystic fibrosis lung disease,” Boucher said. “They also revealed that you have to have long-acting compounds to do this in a way that’s going to be clinically useful.”
The UNC project is an important step toward understanding CF lung disease and producing better treatments, said Tarran, the paper’s first author.
“We showed that long-term treatment may be needed to reverse the disease and that pharmacological agents can be added to the airways to ameliorate CF lung disease,” he said. “Unfortunately for CF patients, the respiratory tract is very good at removing unwanted substances -- except for mucus -- and our data also suggest that many of the compounds currently used in CF trials are rapidly cleared. Thus, future studies will concentrate on developing long-acting substances.”
Clinical testing recently began on a new compound that might create the proper salt balance after being inhaled several times a day by children and adults with the inherited illness, Boucher said.
The National Institutes of Health and the Cystic Fibrosis Foundation support the continuing research.
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