Clues Point to Cystic Fibrosis Treatment


Michael Purdy
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JHMI Office of Public Affairs

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

     The scientists discovered that the genetic mutation that
causes cystic fibrosis prevents an important chemical, adenosine
triphosphate, 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, said
professor of physiology Bill Guggino. 

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

     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 study, reported in the June 30 issue of Cell,
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," said 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 noted 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,"
he said.  "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.