Mar. 17, 1999 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.
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.
"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.
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.
"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.
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.
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.
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.
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.
(A clinical trial directed by other researchers is already testing a drug that suppresses the tyrosine kinase messenger in order to block cancer proliferation.)
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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