Molecular pathway appears crucial in development of pulmonary fibrosis

December 12, 2007

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.
-end-
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.

Massachusetts General Hospital

Related Pulmonary Fibrosis Articles from Brightsurf:

The CNIO pave the way for a future gene therapy to reverse pulmonary fibrosis associated with ageing
''Our results indicate that a new therapy may be developed to prevent the development of pulmonary fibrosis associated with ageing,'' says CNIO's Maria Blasco, principal investigator of the study * Lung tissue of patients with pulmonary fibrosis does not regenerate because the cells involved in lung generation have damaged telomeres, the ends of the chromosomes.

Pulmonary fibrosis treatment shows proof of principle
A pre-clinical study led by scientists at Cincinnati Children's demonstrates that in mice the drug barasertib reverses the activation of fibroblasts that cause dangerous scar tissue to build up in the lungs of people with idiopathic pulmonary fibrosis (IPF).

Pulmonary embolism and COVID-19
Researchers at Henry Ford Health System in Detroit say early diagnosis of a life-threatening blood clot in the lungs led to swifter treatment intervention in COVID-19 patients.

Stem cells from placental amniotic membrane slow lung scarring in pulmonary fibrosis
In a study released today in STEM CELLS Translational Medicine (SCTM), researchers show for the first time how stem cells collected from human amniotic membrane can slow the progression of scarring in pulmonary fibrosis.

Researchers identify key mechanisms involved in pulmonary fibrosis development
Working alongside research groups from Heidelberg, researchers from Charité - Universitätsmedizin Berlin have elucidated the novel disease processes involved in the development of pulmonary fibrosis.

Bacterial protein fragment kills lung cells in pulmonary fibrosis, study finds
A bacterial protein fragment instigates lung tissue death in pulmonary fibrosis, a mysterious disease affecting millions of people worldwide, according to a new study from researchers at the University of Illinois at Urbana-Champaign and Mie University in Japan.

Closing in on liver fibrosis: Detailing the fibrosis process at unprecedented resolution
Today, there is no effective way to treat liver fibrosis.

Inhalation therapy shows promise against pulmonary fibrosis in mice, rats
A new study shows that lung stem cell secretions -- specifically exosomes and secretomes -- delivered via nebulizer, can help repair lung injuries due to multiple types of pulmonary fibrosis in mice and rats.

Cystic fibrosis carriers are at increased risk for cystic fibrosis-related conditions
A University of Iowa study challenges the conventional wisdom that having just one mutated copy of the cystic fibrosis (CF) gene has no effects on a person's health.

Short or long sleep associated with Pulmonary Fibrosis
Scientists have discovered that people who regularly sleep for more than 11 hours or less than 4 hours are 2-3 times more likely to have the incurable disease, pulmonary fibrosis, compared to those that sleep for 7 hours in a day.

Read More: Pulmonary Fibrosis News and Pulmonary Fibrosis Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.