CHAPEL HILL - University of North Carolina at Chapel Hill scientists have discovered how cystic fibrosis -- the most common fatal genetic disease among whites - damages young lungs. The discovery should improve treatment, the researchers say.
"Despite knowing for roughly 10 years what the genetic mutation is that leads to cystic fibrosis, until now we have not understood the basic cause of the damage in the CF lung," said Dr. Richard C. Boucher Jr., Kenan professor of medicine at the UNC-CH School of Medicine. "If you don't understand the root cause of a disease, it's very difficult to treat it. You can only treat the after-effects of the infection."
The chief difference between lung damage in CF and injury to other organs such as the pancreas and gastrointestinal tract is that chronic bacterial infections plague only the former, Boucher explained.
The physician and his colleagues found that a film of liquid only seven microns -- millionths of a meter -- thick coats the airways. Each lung surface cell contains about 200 tiny hair-like structures called cilia that beat about 20 times a second in wavy patterns like wind passing over a wheat field. In a natural cleansing process, the cilia remove mucus and dust, bacteria and other particles trapped within.
"We found that in cystic fibrosis, patients absorb too much fluid from the lung's surface and deplete this liquid layer," Boucher said. "Not having the liquid there prevents the cilia, which are about seven microns tall themselves, from going through their normal beat cycle. Mucus impacts the cilia and flattens them."
In addition, he said, when the lubricating fluid is missing or greatly reduced, the body's backup system for clearing the lungs of debris - coughing - cannot work well either. Instead of being sloughed off during an explosive cough, the mucus just sticks to the airway cells like a paste trapping bacteria and other microorganisms that then reproduce in the lung and cause infection.
A report on the findings appears in Wednesday's (Dec. 23) issue of the journal Cell. Besides Boucher, authors are Drs. Hirotoshi Matsui, Barbara R. Grubb, Robert Tarran, Scott H. Randell, John T. Gatzy and C. William Davis, all current or former faculty and staff at the UNC-CH Cystic Fibrosis/Pulmonary Research and Treatment Center.
In conducting the studies, Randell led the way in developing the first cystic fibrosis culture model that both secretes mucus and transports it just as it moves in the lungs, said Boucher, who directs the center. Matsui and Tarran figured out how to apply a sophisticated confocal microscope to living cultures to measure the height of the lung liquid. Grubb developed an artificial airway model that confirmed the results.
"One of the general principles of the body is that if you don't clear a fluid from an orifice as you normally should and you have a blockage, then you get chronic infection, " he said. "That's true for ear infections, bladder infections and gall bladder infections, and the lung is no different."
Cystic fibrosis patients' bodies remove too much liquid from airway surfaces because of an inability to regulate the amount of salt and water normally there, the physician said.
"This work is so exciting for CF patients because it really lays down a blueprint for new therapies," Boucher said. "We will have to add salt in some way back to the airway surfaces in cystic fibrosis patients so that water will flow back from their bodies to their airways to re-establish this liquid layer. Removing mucus will be comparable to removing a splinter because you can't control an infection you get around a splinter unless you pull it out."
The National Institutes of Health and the Cystic Fibrosis Foundation supported the study.
UNC-CH 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.
Note: Boucher can be reached at 919-966-1077 (w) or 967-5739.
Contact: David Williamson, 919-962-8596 or Mike McFarland, 962-8593.
Journal
Cell