Featured Research

from universities, journals, and other organizations

UCSF Researchers Pinpoint Molecule That Triggers Deadly Progress Of Pulmonary Fibrosis

Date:
February 11, 1999
Source:
University Of California San Francisco
Summary:
Scientists have uncovered crucial steps in a grim molecular dance that asphyxiates more than 5,000 people a year in the United States. The research pinpoints a pivotal protein involved in a multi-step process leading to pulmonary fibrosis, an incurable lung inflammation that eventually robs the lungs of their ability to supply oxygen to the blood.

Scientists have uncovered crucial steps in a grim molecular dance that asphyxiates more than 5,000 people a year in the United States. The research pinpoints a pivotal protein involved in a multi-step process leading to pulmonary fibrosis, an incurable lung inflammation that eventually robs the lungs of their ability to supply oxygen to the blood.

The protein's specific and localized role makes it a prime target for developing a drug to block the severe lung scarring caused by the condition, the scientists conclude.

The research, reported in the February 5 issue of the journal Cell, was led by Dean Sheppard, MD, professor of medicine at the University of California San Francisco (UCSF) and director of the UCSF Lung Biology Center at San Francisco General Hospital Medical Center.

It has been known for more than a decade that a molecule known as TGF Beta plays an essential role in healing damaged tissue throughout the body. The molecule is active too in the debilitating buildup of excessive fibrous scar tissue in the lungs. The difference between restorative scarring and uncontrolled, deadly fibrosis involves the level of activity of TGF Beta, researchers believe.

But what triggers this molecule to develop fibrous tissue in the first place, be it restorative or deadly? Earlier research had concluded that only when enzymes break it down or cut it up, does the TGF Beta protein become active. But working with laboratory cultures of human cells, the UCSF-led research team discovered that a protein called an integrin is essential to activate the TGF Beta molecule, and it accomplishes this neither by breaking down, nor cutting up TGF Beta, but by changing its shape.

Normally part of a larger protein complex, TGF Beta is inactive until it interacts with the alpha v beta 6 integrin, the team found. The integrin lies partly within a cell and partly outside. When it makes contact with the protein complex that includes TGF Beta, it appears to act as a kind of chemical wedge, the researchers discovered, modifying the shape of the protein complex and exposing the TGF Beta site. TGF Beta can then bind with a specific receptor on the surface of lung cells, beginning the buildup of fibrous tissue.

The critical role of the integrin was confirmed in experiments with mice lacking the gene for this protein -- so-called genetic knockout mice. The team showed that in mice lacking this gene, the lungs do not develop pulmonary fibrosis in response to a drug that normally induces the condition.

But there is more to the story. The researchers also discovered that the integrin must interact with parts of a cell's rigid internal scaffolding, known as the cytoskleton, before it can activate TGF Beta. Their experiments support a model of the multi-step process in which one part of the integrin molecule first binds to the protein complex that includes TGF Beta -- outside the cell. This action modifies the integrin so that another part of it can engage with the cytoskeleton inside the cell. This in turn induces the integrin to change the shape of the molecule containing TGF Beta, allowing the TGF Beta to bind to another protein receptor, initiating the buildup of fibrous material.

"TGF Beta is a widespread and potent molecule," said Dean Sheppard. "But if it were able to become active in many places in the body, it would do great damage. The integrin normally allows it to do its work locally, where it is needed."

But even with those elegant controls, TGF Beta sometimes has exaggerated effects. If integrin is essential for activating TGF Beta and triggering the sequence of steps that leads to fibrosis, Sheppard reasons, then a drug that blocks the integrin locally could halt the deadly lung scarring of pulmonary fibrosis. Currently in the U.S., the condition traps more than a hundred thousand people in the grip of gradual suffocation.

"Knowing the role of the integrin, we have a potential target to control TGF Beta activity if it goes awry," Sheppard added. "The mechanism we described shows a way to allow TGF Beta to continue to be activated very restrictively so it can induce healing, while controlling its ability to cause severe damage."

TGF Beta itself might not be as safe a drug target as the integrin, he said, because it is crucial to a number of essential healing and other processes throughout the body.

The researchers further found that knockout mice, lacking the integrin, live full and healthy lives. Normal wound healing apparently is taken over by back-up mechanisms, but significantly, these mice can not develop lung fibrosis.

Lead authors on the Cell paper are John Munger, MD, assistant professor of medicine at New York University School of Medicine; Xiaozhu Huang, MD, assistant research molecular biologist; and Hisaaki Kawakatsu, PhD, postgraduate researcher, both at the UCSF Lung Biology Center (LBC); and Mark Griffiths, MD, PhD, pulmonary physician at Charing Cross Hospital, London.

Other co-authors are Stephen Dalton, MD, PhD, dermatology fellow; Jianfeng Wu, staff research associate; and Naftali Kiminksi, MD, postdoctoral fellow, all at the Lung Biology Center; Jean Pittet, MD, associate professor of anesthesiology, SFGHMC; Chrystelle Garat, MD, post-doctoral fellow, UCSF Cardiovascular Research Institute; Michael Matthay, MD, professor of medicine and senior associate, Cardiovascular Research Institute; and Daniel Rifkin, PhD, professor of cell biology and medicine, New York University School of Medicine.

The research was funded by the National Institutes of Health, the Inger-Ma Sonneborn Fund, and the Wellcome Trust UK.


Story Source:

The above story is based on materials provided by University Of California San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University Of California San Francisco. "UCSF Researchers Pinpoint Molecule That Triggers Deadly Progress Of Pulmonary Fibrosis." ScienceDaily. ScienceDaily, 11 February 1999. <www.sciencedaily.com/releases/1999/02/990211073743.htm>.
University Of California San Francisco. (1999, February 11). UCSF Researchers Pinpoint Molecule That Triggers Deadly Progress Of Pulmonary Fibrosis. ScienceDaily. Retrieved August 23, 2014 from www.sciencedaily.com/releases/1999/02/990211073743.htm
University Of California San Francisco. "UCSF Researchers Pinpoint Molecule That Triggers Deadly Progress Of Pulmonary Fibrosis." ScienceDaily. www.sciencedaily.com/releases/1999/02/990211073743.htm (accessed August 23, 2014).

Share This




More Health & Medicine News

Saturday, August 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Newsy (Aug. 21, 2014) An experimental drug used to treat Marburg virus in rhesus monkeys could give new insight into a similar treatment for Ebola. Video provided by Newsy
Powered by NewsLook.com
Two US Ebola Patients Leave Hospital Free of the Disease

Two US Ebola Patients Leave Hospital Free of the Disease

AFP (Aug. 21, 2014) Two American missionaries who were sickened with Ebola while working in Liberia and were treated with an experimental drug are doing better and have left the hospital, doctors say on August 21, 2014. Duration: 01:05 Video provided by AFP
Powered by NewsLook.com
Cadavers, a Teen, and a Medical School Dream

Cadavers, a Teen, and a Medical School Dream

AP (Aug. 21, 2014) Contains graphic content. He's only 17. But Johntrell Bowles has wanted to be a doctor from a young age, despite the odds against him. He was recently the youngest participant in a cadaver program at the Indiana University NW medical school. (Aug. 21) Video provided by AP
Powered by NewsLook.com
American Ebola Patients Released: What Cured Them?

American Ebola Patients Released: What Cured Them?

Newsy (Aug. 21, 2014) It's unclear whether the American Ebola patients' recoveries can be attributed to an experimental drug or early detection and good medical care. 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