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U-M scientists target key cells and signals that trigger pulmonary fibrosis

24.05.2006
Research could lead to new treatments, diagnostic tests for IPF

Scientists at the University of Michigan Medical School have identified biochemical signals that attract pathogenic cells to damaged lung tissue – one of the first steps in a chain of events leading to a lethal disease called idiopathic pulmonary fibrosis or IPF.

Idiopathic pulmonary fibrosis is a progressive disease that kills 40,000 Americans each year. Exposure to toxic environmental agents like beryllium and silica dust can trigger IPF, but in most cases, its cause remains a mystery.

"The disease is devastating to the patients who have it, and to the physicians who have no effective ways to treat it," says Bethany B. Moore, Ph.D., an assistant professor of internal medicine at the U-M Medical School. Working with Galen B. Toews, M.D. – a professor of internal medicine and chief of pulmonary and critical care medicine – and other Medical School researchers, Moore studies the cells and signaling pathways involved in IPF.

"IPF gradually destroys air sacs in the lung and replaces them with scar tissue – making it difficult and eventually impossible for patients to breathe," Moore says. "Most patients aren’t diagnosed until the disease is in an advanced stage, and they often die within two years of diagnosis."

By learning more about the basic mechanisms of the disease, U-M scientists hope to uncover new information that could lead to therapeutic drugs to block progressive lung damage or diagnostic tests to make early detection possible.

Moore will present the latest results from her IPF research in a May 23 poster presentation at the American Thoracic Society meeting taking place May 19-24 in San Diego.

Moore studies fibrocytes – primitive cells derived from bone marrow that help repair and restore damaged tissue in the body. When lung tissue is injured, damaged cells send out biochemical distress signals that draw fibrocytes from the bloodstream to the injured area. Once in the lung, fibrocytes turn into fibroblasts – cells that secrete collagen, growth factors and other substances to form scar tissue and help heal the damaged lung. Once repairs are complete, chemical signaling molecules called prostaglandins shut down the influx of fibrocytes and turn off the fibrotic response.

"In pulmonary fibrosis, for reasons we don’t understand, this fibrotic or scar-forming process never shuts down," Moore explains. "Collagen and scar tissue build up in the interstitial spaces between lung cells, making lung tissue sticky and difficult to expand when you inhale. As the disease progresses, people with IPF slowly suffocate to death." In her ATS presentation, Moore will present new evidence indicating that lipid mediators called cysteinyl leukotrienes may be responsible for the inappropriate activation of fibrocytes in fibrotic lungs, while prostaglandins can inhibit fibrocyte function.

"These findings suggest that therapies to block leukotrienes or to enhance prostaglandins may be beneficial to patients suffering from IPF," Moore explains.

In earlier research, Moore discovered that a receptor molecule called CCR2 must be present on the fibrocyte’s surface, in order for fibrosis to begin. Laboratory mice without the CCR2 molecule were unable to attract fibrocytes and did not develop pulmonary fibrosis after lung injury.

When Moore transferred fibrocytes containing the CCR2 receptor into healthy mice, the mice developed more severe fibrosis after lung injuries than mice that did not receive the fibrocyte transplant.

Moore also found that a specific ligand, or chemical signal, called CCL12 in mice, is produced by epithelial cells in damaged lung tissue. Moore’s research indicates that CCL12’s signal recruits fibrocytes from the bloodstream to the area of tissue damage, and helps trigger the fibrotic process.

After Moore’s research indicated the critical role played by fibrocytes in the development of IPF, U-M clinicians began screening blood samples from U-M patients with the disease. According to Moore, they found fibrocytes from IPF patients produced three times the normal amount of collagen.

"Fibrocytes have at least six different receptor molecules on their surface, so there are certainly multiple signaling pathways involved in the development of IPF," Moore says. "But now we know that preventing the binding between the CCL12 ligand and the CCR2 receptor in mice can limit the disease’s development."

The CCL12 ligand in mice is virtually identical to the CCL2 ligand in humans, which is known to be involved in other human lung diseases, according to Moore. So antibodies or small molecules capable of blocking CCL2’s signal could be promising candidates for new drug discovery.

"We may not be able to stop the initial disease process, but perhaps we could keep it from progressing so rapidly," Moore added. "It’s a first step, but an important one, in solving the mystery of this disease. Right now, continued research is the only hope we can offer IPF patients."

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

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