Feb. 11, 1999 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.
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