- Scientists have discovered the deadly
trigger that can initiate uncontrolled mucus production, a malady that
kills millions of people a year by blocking their airways. Chronic bronchitis,
cystic fibrosis and acute asthma, all caused by blocked airways, affect
about 20 million people in the U.S. There are no known cures.
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- The new finding by researchers at the
University of California San Francisco points to a straightforward strategy
to prevent mucus from accumulating and blocking airways. The researchers
found that a well-studied cell messenger signals a mucus-producing gene
to turn on, and they suggest that drugs targeting this messenger can keep
the gene switched off.
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- "Hypersecretory diseases like cystic
fibrosis and chronic bronchitis take a terrible toll, but no drugs have
ever been developed to cure them," said Jay Nadel, M.D., UCSF professor
of medicine and physiology. "Now that we know the chemical cascade
that activates this mucus gene we should be able to develop strategies
to control mucus production and prevent it from blocking airways."
Nadel is senior author of a report on the research appearing in the current
issue of the Proceedings of the National Academy of Sciences.
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- Hypersecretory diseases have been untreatable
because no one knew what triggered mucus-producing genes, nor how to block
this action. In these diseases, epithelial cells develop into mucus-filled
"goblet" cells, and when the goblet cells secrete the viscous
mucus, it expands many hundred-fold in the water along the airway surface,
blocking small air passages.
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- "Victims literally drown in their
own secretions," Nadel explained. In the UCSF research, rats that
were induced to turn on mucus genes developed goblet cells. But when the
animals were treated with a drug to block a cell messenger known as tyrosine
kinase, the mucus genes were turned off. Nadel hopes further animal studies
and then clinical trials of this strategy will lead quickly to the first
effective treatment to arrest the deadly mucus buildup of hypersecretory
diseases.
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- The UCSF researchers discovered that
a mucus gene called MUC5AC is activated by a sequence of molecular interactions
that starts on the surface of airway epithelial cells. In a series of experiments
with rats and with human cells in culture, they found that a protein known
as epidermal growth factor receptor, or EGF-R, triggers the sequence of
chemical steps. EGF-R is not common in the airways but another molecule,
known as tumor necrosis factor alpha, stimulates production of EGF-R in
airway epithelial cells.
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- Once present, EGF-R is activated by binding
with two other molecules, called epidermal growth factor and transforming
growth factor alpha. Like EGF-R, these molecules are not common in healthy
airways, but are produced when tissues become inflamed by such insults
as cigarette smoke or some bacteria and viruses, Nadel explained.
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- In the UCSF experiments, once EGF-R binds
to its two molecular partners, or ligands, the EGF receptor complex sends
a signal to the cell nucleus to turn on the mucus gene, MUC5AC. The messenger,
the researchers found, is a much-studied enzyme known as EGF receptor tyrosine
kinase.
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- The site where the mucus production sequence
begins had not been known before, nor had the role of tyrosine kinase as
the key "second messenger" in this cascade that triggers the
mucus gene. Tyrosine kinase serves as a signal in many internal cellular
communications, making it a promising target for potential drugs to control
messages gone awry.
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- (A clinical trial directed by other researchers
is already testing a drug that suppresses the tyrosine kinase messenger
in order to block cancer proliferation.)
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- Lead author on the PNAS report is Kiyoshi
Takeyama, M.D., Ph.D., postdoctoral scientist at UCSF's Cardiovascular
Research Institute (CVRI). Other research team members and co-authors on
the report, all at UCSF, are Karim Dabbagh, Ph.D., postdoctoral scientist
at the CVRI; Heung-Man Lee, M.D., Ph.D., associate professor, and Carlos
Agusti, M.D., Ph.D., assistant professor, both of medicine and physiology.
Also: James Lausier, Iris Ukei and Kathleen Grattan, UCSF technicians in
medicine and physiology.
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