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
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Contact: Wallace Ravven
wravven@itsa.ucsf.edu
415-476-2557
University of California - San Francisco
5-Feb-1999