September 28, 1995
Media Contact: Michael Purdy
Phone: (410) 955-8725
E-mail: mpurdy@welchlink.welch.jhu.edu

A new finding about the complex effects of cystic fibrosis may ultimately make it easier to treat the disorder, basic researchers at Johns Hopkins report.

Hopkins scientists discovered that the genetic mutation that causes cystic fibrosis prevents an important chemical, adenosine triphosphate (ATP), from reaching the surface of lung cells.

If researchers can create an aerosol form of ATP, patients should be able to inhale it to ease cystic fibrosis symptoms, according to Bill Guggino, Ph.D., a Hopkins professor of physiology.

"This is very basic science that we're doing here, but it has strong implications for treatment of the disease," Guggino says.

Approximately 40,000 persons in the United States have cystic fibrosis. In addition to digestive difficulties, the inherited disorder causes a buildup of unusually thick mucus in the lungs. This buildup contributes to repeated infections and inflammation that destroy lung tissues, shortening the life span of cystic fibrosis patients.

Scientists located the cystic fibrosis gene in 1989, and later linked it to chloride channels, special openings in the surfaces of cells.

Chloride channels release charged salt particles from cells; outside the cells, the particles draw water from the blood, supplying moisture for the body's lubricants and secretions.

Two seemingly conflicting sets of clues about what the gene actually did for chloride channels emerged.

One set suggested that the gene built chloride channels; another, that the gene regulated the rate of construction of a second type of chloride channel.

Scientists had begun to favor the "gene-as-builder" theory, but in the June 30 issue of Cell, Hopkins researchers showed that the gene is both a builder and a regulator.

"Other researchers had established that the gene builds one type of chloride channel," says Guggino. "We showed that this chloride channel releases more than just salt ions; it also releases ATP, which binds with the surface of the cell to activate a different type of chloride channel."

ATP may also help regulate a third channel that lets cells absorb water. All three channels work together to keep mucus on the surface of lung cells moist but not so wet that the airways fill with water. In cystic fibrosis patients, this delicate balancing act is disrupted.

Guggino notes that the new discovery may just be the second link in a long chain of effects created by the cystic fibrosis mutation.

"The airway has many mechanisms for protecting itself from infection, and this gene may be involved with a number of them," says Guggino. "We know the gene's role in mucus lubrication relatively well, but the gene may also play a role in determining the composition of sugars on the surface of airway cells, and in the airway's inflammatory reaction to infection."

Subtle differences in cell surface sugar compositions can make a big difference in susceptibility to infection, Guggino explains. Airborne bacteria must bind to the cell surface to infect cells; the wrong mix of sugars could change the surface of the cell from a door locked tight against infection into a wide-open welcome mat.

Scientists know less about the gene's potential relationship to inflammation, but they suspect that lung tissues in cystic fibrosis become damagingly over-inflamed in response to infection. Guggino's research was funded by the National Institutes of Health and the Cystic Fibrosis Foundation. Other authors on the paper were Erik Schwiebert, Marie Egan, Tae-Ho Hwang, Stephanie Fulmer and Sandra Allen, all of Hopkins; and Garry Cutting , M.D., of Yale University.

-- JHMI --
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