Two-drug treatment may block source of asthma and chronic bronchitis

February 01, 2006

Current treatments for asthma and chronic bronchitis aren't able to address the ultimate source of the problem--they can only alleviate symptoms. But researchers at Washington University School of Medicine in St. Louis have gone to the root of these disorders and found a two-drug treatment that could potentially restore patients' troubled airways to healthy function.

Their study appears in the February 1 issue of the Journal of Clinical Investigation.

Michael J. Holtzman, M.D., and colleagues discovered that some cells that line the air passages of the lung transform into another cell type in mice and humans with these disorders. This cellular transformation had never before been recognized and is responsible for overproduction of mucus in the airways.

The researchers found that preventing the harmful transformation of lining cells could be accomplished with two drugs, and they assert that these drugs may possibly be used in combination to normalize the airway lining in asthma and chronic bronchitis sufferers.

"In these disorders, shortness of breath and cough are related to hypersecretion of mucus in the airway," says Holtzman, the Selma and Herman Seldin Professor of Medicine and director of pulmonary and critical care medicine. "Physicians prescribe anti-inflammatory steroids and bronchodilators to ease breathing difficulties, but these medications don't specifically reduce mucus production or secretion. Our research addresses this aspect of the problem."

In mice with a chronic lung condition resembling asthma and chronic obstructive pulmonary disease (COPD), the researchers saw that the airway lining maintained an overabundance of mucus-producing cells (called goblet cells for their cup-like shape). Further investigation showed that goblet-cell buildup resulted from two cellular mechanisms. One mechanism allows for the prolonged survival of cells with cilia, tiny hairs that help sweep debris out of the lungs. The other mechanism encourages the ciliated cells to transform into goblet cells.

The researchers were the first to demonstrate this transformation from ciliated to goblet cells in a model of chronic lung disease. They also demonstrated that a similar process may occur in humans with asthma and COPD, a disease classification that includes chronic bronchitis.

"In some people, stimuli such as viral infections seem to cause a chronic excess of goblet cells and lead to persistent breathing disorders," Holtzman says. "We showed that you can block the excess of ciliated and goblet cells using a combination of two types of inhibitors."

The first of these inhibitors is newly developed and is able to impede the activity of epidermal growth factor receptor (EGFR). EGFR was persistently overactive in the ciliated airway cells in mice with the asthma-like condition. This chronic activity protected the ciliated cells from normally programmed cell death and allowed the cells to accumulate to higher than normal levels. By blocking EGFR, the inhibitor prevented the buildup of ciliated cells.

The second inhibitor the researchers tested interferes with signaling pathways activated by an immune-system protein known as interleukin-13 (IL-13). They found that IL-13 elicited the crucial change from ciliated to goblet cells in mouse airways and human airway cells in culture. Interfering with IL-13 prevented this transformation from one cell type to the other--a process known as transdifferentiation.

"Finding this sequence of events--the increase in the level of ciliated cells and then the transdifferentiation of these cells to goblet cells--opens up new treatment options that may be more effective than those tried in the past," Holtzman says. "We've shown that if you combine the EGFR and IL-13 inhibitors in a rational way, you can restore the normal architecture of the airway lining. But you have to use the combination to fully correct the abnormalities."

Holtzman believes the study's findings could readily translate into clinical treatments for asthma, COPD and other chronic airway diseases because EGFR antagonists and IL-13 inhibitors are now undergoing separate testing in the treatment of chronic airway diseases by several drug companies. The present study results should allow for better design and assessment of these inhibitors when used either alone or in combination.

Tyner JW, Kin EY, Ide K, Pelletier MR, Roswit WT, Morton JD, Battaile JT, Patel Ac, Patterson A, Castro M, Spoor MS, You Y, Brody SL, Holtzman MJ. Blocking airway mucus cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferention signals. Journal of Clinical Investigation February 2006;116(2).

Funding from the National Institutes of Health (Heart, Lung, and Blood Institute) and the Alan A. and Edith L. Wolff Charitable Trust supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

Related Asthma Articles from Brightsurf:

Breastfeeding and risks of allergies and asthma
In an Acta Paediatrica study, exclusive breastfeeding for the first 3 months was linked with a lower risk of respiratory allergies and asthma when children reached 6 years of age.

Researchers make asthma breakthrough
Researchers from Trinity College Dublin have made a breakthrough that may eventually lead to improved therapeutic options for people living with asthma.

Physics vs. asthma
A research team from the MIPT Center for Molecular Mechanisms of Aging and Age-Related Diseases has collaborated with colleagues from the U.S., Canada, France, and Germany to determine the spatial structure of the CysLT1 receptor.

New knowledge on the development of asthma
Researchers at Karolinska Institutet in Sweden have studied which genes are expressed in overactive immune cells in mice with asthma-like inflammation of the airways.

Eating fish may help prevent asthma
A scientist from James Cook University in Australia says an innovative study has revealed new evidence that eating fish can help prevent asthma.

Academic performance of urban children with asthma worse than peers without asthma
A new study published in Annals of Allergy, Asthma and Immunology shows urban children with poorly controlled asthma, particularly those who are ethnic minorities, also suffer academically.

Asthma Controller Step Down Yardstick -- treatment guidance for when asthma improves
The focus for asthma treatment is often stepping up treatment, but clinicians need to know how to step down therapy when symptoms improve.

Asthma management tools improve asthma control and reduce hospital visits
A set of comprehensive asthma management tools helps decrease asthma-related visits to the emergency department, urgent care or hospital and improves patients' asthma control.

Asthma linked to infertility but not among women taking regular asthma preventers
Women with asthma who only use short-acting asthma relievers take longer to become pregnant than other women, according to research published in the European Respiratory Journal.

What are the best ways to diagnose and manage asthma?
A team of experts from The University of Texas Medical Branch at Galveston examined the current information available from many different sources on diagnosing and managing mild to moderate asthma in adults and summarized them.

Read More: Asthma News and Asthma Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to