The discovery was reported in a study posted online Sept. 14 by the Journal of Clinical Investigation. The new research sheds light on what has been a medical mystery - the precise biological reasons that the lungs in people with asthma, cystic fibrosis and other respiratory ailments clog with thick mucus.
Identifying the genetic circuits that cause mucous hyper-production gives researchers potential targets for new therapies to moderate or stop it, said Jeffrey Whitsett, M.D., the head of Neonatology, Perinatal and Pulmonary Biology at Cincinnati Children's Hospital Medical Center and the study's senior investigator.
"Everyone has had a stuffed up nose and cough after two or three weeks of a bad cold and most over-the-counter cold medications deal with mucus," Whitsett explained. "We still don't have effective therapies for removing excess mucous, whether it's someone with a cold or chronic lung disease. That's why we still tap on the chests of kids with cystic fibrosis to try and clear it."
The current study provides an entirely new understanding of how certain cells promote chronic lung infection and excess mucus production. Scientists previously thought that, after airways were attacked by an allergic response or inflammation, mucus cells (known as goblet cells) divided and proliferated at a very fast rate - a process known as hyperplasia. Instead, the Cincinnati Children's team discovered that beneficial lung cells, called Clara cells, instead change their cell type to become goblet/mucous cells in a process called metaplasia.
Dr. Whitsett and his colleagues also found the metaplasia process in this instance to be reversible. Goblet cells can change back to Clara cells if the detrimental genetic influence is blocked, highlighting a possible pathway for new treatments, according to Dr. Whitsett, who also is executive director of the Perinatal Institute at Cincinnati Children's.
The study identifies a transcription factor, SPDEF, as the master gene that regulates a chain of dozens of downstream genes involved in mucus production. SPDEF is an active player in other organ systems that need to produce mucus for normal function, such as the digestive system. In healthy lungs, however, the researchers report the gene is mostly quiet, as healthy lungs don't produce significant amounts of mucus.
Using an egg white protein called ovalbumin to induce an allergic reaction and inflammation in the lungs of mice, the researchers observed a dramatic elevation in the expression of SPDEF in the lung tissues of the affected animals. The animals also experienced hyper-production of thick mucus in their lungs. In mice where the SPDEF gene was switched off, inflammation and excessive mucus production did not occur, demonstrating the gene's potential as therapeutic or diagnostic target. Mice lacking SPDEF were unable to increase mucus production or develop goblet cells.
In mice where respiratory inflammation and excessive mucus production were present, the researchers report that SPDEF turned off genes involved in biological processes that help protect lung tissues from infection and damage. Conversely, SPDEF activated genes that promote inflammation and excessive mucus - in particular FOXA3, AGR2 and mucins.
By composition, mucus is a sugar-coated collection of large proteins that, in healthy conditions, help the body defend itself by collecting and then clearing out contaminants. In the case of AGR2 for example, the gene helps assemble mucus proteins by folding together different molecules. When SPDEF is over-expressed, it results in increased production of AGR2, which in turn promotes an over-abundance of protein folding and mucus production.
Dr. Whitsett cautioned it will be several years before the research results in a specific therapeutic approach that can be tested in people. In the meantime, his team has received several significant grants to conduct more extensive studies into the various genetic and molecular influences that control, or are controlled by, SPDEF and involved in excess mucus production.
The first author on the current study was Gang Chen, a graduate student in Dr. Whitsett's laboratory. The laboratory's research is supported by funding from the National Institutes of Health and the Cystic Fibrosis Foundation. The study was done in collaboration with the Netherlands Institute of Developmental Biology, with the research there being led by Dr. Hans Clevers.
About Cincinnati Children's
Cincinnati Children's Hospital Medical Center is one of 10 children's hospitals in the United States to make the Honor Roll in U.S. News and World Reports 2009-10 America's Best Children's Hospitals issue. It is #1 ranked for digestive disorders and is also highly ranked for its expertise in respiratory diseases, cancer, neonatal care, heart care, neurosurgery, diabetes, orthopedics, kidney disorders and urology. One of the three largest children's hospitals in the U.S., Cincinnati Children's is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health.
President Barack Obama in June 2009 cited Cincinnati Children's as an "island of excellence" in health care. For its achievements in transforming health care, Cincinnati Children's is one of six U.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases. Additional information can be found at www.cincinnatichildrens.org.
Nick Miller | EurekAlert!
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