Featured Research

from universities, journals, and other organizations

Drugs limiting excess mucus could save lives

Date:
November 26, 2012
Source:
Washington University in St. Louis
Summary:
Respiratory conditions that restrict breathing such as asthma and chronic obstructive pulmonary disease (COPD) are common killers worldwide. But no effective treatments exist to address the major cause of death in these conditions – excess mucus production. Now, researchers have described the molecular pathway responsible for excess mucus in airway cells and have used that information to design a series of new drugs that inhibit that pathway.

Michael Holtzman, MD, and his colleagues designed drugs (yellow) that bind with the MAPK13 enzyme (grey) to limit excess mucus production in airway cells. According to Holtzman, the drugs could help patients with life-threatening respiratory conditions including COPD and asthma.
Credit: Michael J. Holtzman, MD

Respiratory conditions that restrict breathing such as asthma and chronic obstructive pulmonary disease (COPD) are common killers worldwide. But no effective treatments exist to address the major cause of death in these conditions -- excess mucus production.

"There is good evidence that what kills people with severe COPD or asthma is mucus obstructing the airway," says Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine at Washington University School of Medicine in St. Louis. "It's a huge unmet medical problem and is only increasing in this country and throughout the world."

Now, Holtzman and his colleagues have described the molecular pathway responsible for excess mucus in airway cells and have used that information to design a series of new drugs that inhibit that pathway.

Their study appears online Nov. 26 in the Journal of Clinical Investigation.

Chronic respiratory disease, especially COPD, is the third leading cause of death in the United States and worldwide. Smoking and exposure to pollution are major causes of these diseases. Related conditions that affect the respiratory airways, like asthma and bronchitis, are also among the most common causes of human disease in adults and children. The morbidity and mortality from these conditions is closely linked to excess mucus production that blocks the airways and prevents normal breathing. However, there are no effective treatments to address the overproduction of airway mucus.

As part of the new research, the scientists discovered that a critical signaling molecule, CLCA1, has a special role in the mucus pathway. They showed that CLCA1 allows a protein known as IL-13 to turn on the major mucus gene in airway cells. The researchers also showed that CLCA1 needs help from an enzyme called MAPK13.

Although there were no existing drugs that acted against MAPK13, Holtzman says there were several that inhibit a similar enzyme known as MAPK14, which differs slightly in structure.

"We could take advantage of the MAPK14 inhibitors that were already known," Holtzman says. "These drugs bind to a specific pocket in MAPK14 to block its activity. For MAPK13, that pocket itself has some obstructions making it more crowded and harder to access, so these older drugs can't fit into the pocket to block activity."

So Holtzman and his team built drugs with slimmer structures that could avoid the obstacles and better fit into the protein pocket of MAPK13.

"We sculpted the drugs so they're better able to bind in the MAPK13 pocket," Holtzman says. "And we showed that the new shape translates into more potent and effective blockade of MAPK13 activity. It's drug discovery that takes advantage of biology and chemistry, and it takes a very special team to do that."

Indeed, the results show that some of their newly designed MAPK13 inhibitors reduced mucus production in cultures of human airway cells by 100 fold.

Importantly, Holtzman says that this work had to be done in human cells because commonly used lab animals have different wiring for the mucus production circuit. For example, MAPK13 inhibitors were not effective in mice because other types of CLCA and MAPK proteins could continue to make excess mucus.

"We recognized that we had to work directly in human cells to figure out the control system," Holtzman says. "We then looked at lungs from patients with very severe COPD who were at the last resort of lung transplantation. In these diseased lungs, we found too much mucus, too much CLCA1 and over-activated MAPK13. What we observed in isolated human cells translated to a devastating disease in real life."

Beyond COPD and asthma, Holtzman also sees a possible role for MAPK13 inhibitors in related conditions with excess mucus production, like cystic fibrosis and even the common cold.

"The big killer is COPD," Holtzman says. "But other extra-mucus conditions can also be life threatening. And we know from our studies that respiratory viral infections and allergies are potent activators of this same pathway for mucus production. Since the new inhibitors would be active in both the upper and lower airways, they could impact a wide set of respiratory illnesses."


Story Source:

The above story is based on materials provided by Washington University in St. Louis. The original article was written by Julia Evangelou Strait. Note: Materials may be edited for content and length.


Journal Reference:

  1. Alevy YG, Patel AC, Romero AG, Patel DA, Tucker J, Roswit WT, Miller CA, Heier RF, Byers DE, Brett TJ, Holtzman MJ. IL-13 induced airway mucus production is attenuated by MAPK13 inhibition. Journal of Clinical Investigation, Nov. 26, 2012

Cite This Page:

Washington University in St. Louis. "Drugs limiting excess mucus could save lives." ScienceDaily. ScienceDaily, 26 November 2012. <www.sciencedaily.com/releases/2012/11/121126130930.htm>.
Washington University in St. Louis. (2012, November 26). Drugs limiting excess mucus could save lives. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2012/11/121126130930.htm
Washington University in St. Louis. "Drugs limiting excess mucus could save lives." ScienceDaily. www.sciencedaily.com/releases/2012/11/121126130930.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

Reuters - US Online Video (Aug. 30, 2014) California lawmakers pass a bill requiring universities to adopt "affirmative consent" language in their definitions of consensual sex, part of a nationwide drive to curb sexual assault on campuses. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
New Drug Could Reduce Cardiovascular Deaths

New Drug Could Reduce Cardiovascular Deaths

Newsy (Aug. 30, 2014) The new drug from Novartis could reduce cardiovascular deaths by 20 percent compared to other similar drugs. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins