Molecular Pathway appears crucial in Development of Pulmonary Fibrosis

A study led by Massachusetts General Hospital (MGH) researchers may have found a key mechanism underlying idiopathic pulmonary fibrosis (IPF), a usually fatal lung disease for which transplantation is the only successful treatment. The investigators found that a specific molecular pathway appears responsible for key aspects of the scarring of lung tissue that characterizes IPF, the cause of which is currently unknown. The results will appear in the January issue of Nature Medicine and have received early online release.

"Identifying the key role of this pathway in the development of fibrosis gives us an exciting new target for devising treatments," says Andrew Tager, MD, of the MGH Pulmonary and Critical Care Unit, who led the study. "An agent that blocks this pathway is already being developed as a potential cancer treatment, and we're hoping to be able to test it in our animal model of IPF to determine whether it might be a candidate for trials in patients."

About 50,000 new cases of IPF are diagnosed in the U.S. each year, primarily in people aged 50 to 75. While some patients may survive for extended periods, in others the diseases progresses rapidly, leading to death in an average of 3 to 5 years. Theories about the cause of IPF previously focused on chronic inflammation of the lungs, but recent evidence has suggested that an abnormal healing response to some sort of lung injury may be responsible.

The primary characteristic of IPF is scarring (fibrosis) of the lung surface, rendering it unable to transmit oxygen into the bloodstream. In any part of the body, scarring occurs when cells called fibroblasts, an important part of normal wound healing, make collagen to reinforce the healing matrix that forms over damaged tissue. Normally scarring is limited, but if too many fibroblasts travel to the site of an injury, large amounts of collagen can be deposited, producing excessive, fibrotic scarring. Fibroblasts are known to be present in affected lung tissue in IPF, and previous studies showed that the activity of factors that attract fibroblasts to the site of an injury rises with the severity of the disease. The current study was designed to determine which specific "chemoattractants" were associated with IPF, something not previously known.

Analysis of fluid from the lung surfaces of a mouse model of pulmonary fibrosis suggested that the activity of lysoposphatidic acid (LPA), acting through its receptor LPA1, was responsible for attracting fibroblasts in the disorder. This association was supported by the fact that a strain of mice lacking the gene for LPA1 did not develop pulmonary fibrosis when treated with a compound that usually causes the disease in the animals. Lung fluid samples from human IPF patients not only had significantly higher levels of LPA than control samples, laboratory tests showed that patient samples attracted fibroblasts while fluid from controls did not. In addition, an agent that blocks the LPA1 receptor eliminated the ability of fluid from IPF patients to attract fibroblasts.

"These results indicate that the LPA-LPA1 pathway is responsible for the abnormal migration of fibroblasts into the lungs in IPF, an absolutely crucial step in the development of fibrosis," says Andrew Luster, MD, PhD, senior author of the study. "This pathway appears to be involved in several steps in the development of fibrosis, including the leaking of blood vessels, which is why the LPA1 knockout mice are so dramatically protected. If we're right, then targeting this pathway should be a very exciting new therapeutic strategy for IPF." Luster is director of the MGH Center for Immunology and Inflammatory Disease (CIID) and a professor of Medicine at Harvard Medical School (HMS). Tager is also associated with the MGH CIID and has opened a clinic focused on pulmonary fibrosis and related lung diseases. He is an assistant professor of Medicine at HMS.

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