Cystic Fibrosis, a fatal lung disease striking 1 in 2,500 people, may be caused by a failure of the cilia to maintain the level of water associated with the mucus in the lungs, causing the natural mucus to thicken and become infected with bacteria, ultimately leading to death, Yale researchers report.
Cilia are hair-like structures projecting from many of the cells in the body. They function both to move fluids over cell surfaces and in a sensory capacity.
In 1988, researchers determined that Cystic Fibrosis was due to defects in the gene for the Cystic Fibrosis transmembrane conductance regulator channel (CFTR). CFTR is a passageway through the cell membrane that allows chloride ions to pass back and forth across the cell surface to keep cells in ionic balance.
Other researchers later found that the problem of "sticky mucus" in Cystic Fibrosis lung disease was probably related to the water layer between the mucus and the cell surface. This water layer provides the lubrication that makes it possible for the cilia to beat and thereby propel the mucus, and any bacteria contained in it, into the throat and out of the body. Because the chloride ions that pass through the CFTR channel regulate the height of this water layer, Cystic Fibrosis patients appear to have decreased water on the surface of their airways. This in turn causes the mucus to thicken, preventing the cilia from moving the mucus out of the lungs, and results in a fertile ground for growth of bacteria that ultimately are fatal.
Studies led by Lotte Pedersen and Stefan Geimer, postdoctoral research associates in Professor Joel Rosenbaum's laboratory in the Department of Molecular, Cellular and Developmental Biology at Yale, now show that the CFTR channels are present principally on the cilia that cover the surface of the cells in the airways.
"The cilia cover the surface of most cells in the airways and poke right into the water layer," Pedersen says. "It makes a lot of sense that CFTR is present there."
Researchers studying Cystic Fibrosis lung disease initially thought the problem was with the movement of the cilia, but this turned out not to be the case because when the sticky mucus was removed the cilia moved normally. CFTR channels function when the cell senses that the concentration of salt or water in the water layer is not normal, and then sends a signal to CFTR to let chloride ions flow through to correct the defect. The way the cell senses its aqueous environment has so far been a mystery.
Rosenbaum says that in other life forms, cilia and flagella are osmotic sensors and can detect whether the water is too salty or too dilute. If there are defects in genes coding for these cilia sensors, the organisms can no longer sense their surroundings.
"Certain organisms can't back away from a noxious environment," he notes. "We propose that the cilia in the airways are also sensory and that they are involved in regulating the salt and water concentration of the water layer. Although the cilia are present in Cystic Fibrosis, they either lack or have defective chloride channels that are unable to regulate the water environment."
Rosenbaum says the finding means that researchers should again look at the role of cilia in Cystic Fibrosis, not in terms of the cilia's ability or failure to move the mucus out of the lungs, but rather at how the cilia are sensing the water environment.
"This doesn't tell us how the disease actually occurs, but it points us in a new direction," he says.
The findings were presented in December at a meeting of the American Society for Cell Biology in San Francisco, California.
-- By Jacqueline Weaver
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