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.

Additional co-authors of the study are Peter LaCamera, Barry Shea, Gabriele Campanella, John Wain, Banu Karimi-Shah, Nancy Kim, and William Hart, of the MGH; Moises Selman, National Institute for Respiratory Disorders, Mexico; Zhenwen Zhao, and Yan Xu, Indiana University School of Medicine; Vasiliy Polosukhin, and Timothy Blackwell, Vanderbilt University School of Medicine; Annie Pardo, National Autonomous University of Mexico; and Jerold Chun, Scripps Research Institute. The study was supported by grants from the Pulmonary Fibrosis Foundation, the American Lung Association, the Nirenberg Center for Advanced Lung Disease, the National Autonomous University of Mexico, and the U.S. National Institutes of Health.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.