Gentic circuits that cause mucous hyper-production identified

Sep 15 2009

Scientists have identified the main genetic switch that causes excessive mucous in the lungs, a discovery that one day could ease suffering for people with chronic lung diseases like asthma and cystic fibrosis, or just those fighting the common cold.

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 mucous.

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 mucous 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 mucous production. SPDEF is an active player in other organ systems that need to produce mucous 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 mucous.

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 mucous in their lungs. In mice where the SPDEF gene was switched off, inflammation and excessive mucous production did not occur, demonstrating the gene's potential as therapeutic or diagnostic target. Mice lacking SPDEF were unable to increase mucous production or develop goblet cells.

In mice where respiratory inflammation and excessive mucous 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 mucous - in particular FOXA3, AGR2 and mucins.

By composition, mucous 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 mucous 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 mucous 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 mucous production.