A research team at Yale has found that blocking a kind of cell death called apoptosis in fibrotic diseases of the lung, also blocks the fibrosis, opening new ways of looking at treatment for lung diseases such as pulmonary fibrosis.
Published in the August 2 issue of the Journal of Experimental Medicine, the study, led by Jack A. Elias, M.D., of Yale, examined how a molecule called TGF-beta causes apoptosis and abnormal scarring in the lungs.
Elias said there are a variety of human diseases where normal tissue is replaced with scar tissue that doesn't function the same way as the original tissue. This results in dysfunction of the skin or other involved organ. People can develop fibrosis of the skin, which leads to conditions like sclerodoma, where the skin thickens. When this occurs in the lungs, it is called pulmonary fibrosis. In pulmonary fibrosis, the normally thin lung tissue is replaced with thick, coarse scar tissue that impairs the flow of oxygen into the blood and leads to a loss of lung function.
"Most people think that an excess of TGF-beta is the cause of the fibrosis, so we explored how TGF-beta actually does this," said Elias, who, along with Chun Geun Lee, M.D. and the rest of the team, created a transgenic mouse and targeted TGF-beta into the mouse lungs. This overexpression of TGF-beta caused pulmonary fibrosis in the mouse. This unique experimental system allowed the research team to turn the gene on and off at will. They could time when the production of TGF-beta started and watch the sequence of events that occurred before pulmonary fibrosis developed.
"We discovered that TGF-beta causes the epithelial cells in the lung to die via apoptosis," said Elias. "Up until now, no one has really understood that this cell death comes before and is required for the development of pulmonary fibrosis. This is exciting because when biopsies of the lung from humans with pulmonary fibrosis are examined, fibrosis and apoptosis are observed simultaneously."
"We now know the mechanism involved in apoptosis in the lungs," Elias added. "We could potentially treat fibrotic disorders in the lung by blocking apoptosis and no one has ever done that before."
This latest finding by Elias and his team is part of a large body of work dedicated to research into lung diseases such as asthma and pulmonary fibrosis. The ultimate goal is development of new treatments for these disorders.
Other authors on the study include Soo Jung Cho, Min Jong Kang, Svetlana P. Cahpoval, Patty J. Lee, Paul W. Noble, Teshome Yehualaeshet, Bingeng Lu, Richard A. Flavell, and Robert J. Homer of Yale; and Jeffrey Milbrandt of Washington University School of Medicine.
Citation: J. Exp. Med. Volume 200, Number 3, August 2, 2004
Karen N. Peart