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Molecular pathway appears crucial in
development of pulmonary fibrosis
Discovery may provide new
therapeutic target for dangerous lung diseases
BOSTON - 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.
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.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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