Genetic Switch May Provide Treatment Target for Excess Mucus in Lung Disease

Scientists at the Cincinnati Children’s Hospital have identified the main genetic switch that causes excessive mucus in the lungs, a discovery that elucidates the biological reasons that the lungs in people with asthma, cystic fibrosis and other respiratory ailments become obstructed with thick mucus, which could lead to new therapeutic pathways. Scientists previously thought that after airways were attacked by an allergic response or inflammation, goblet cells divided and proliferated by hyperplasia. The current team discovered that in fact, Clara cells change their cell type to become goblet cells via metaplasia and found the 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. The study, details of which were published in the 14th September online edition of the Journal of Clinical Investigation (10.1172/JCI39731), identified a transcription factor, SPDEF, as the master gene that regulates a chain of many downstream genes involved in mucus production.

SPDEF is actively involved 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. Using ovalbumin to induce an allergic reaction and inflammation in the lungs of mice, the investigators observed a dramatic elevation in SPDEF expression in the lung tissues of affected animals. The animals also experienced hyperproduction 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 a 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 reported that SPDEF turned off genes involved in biological processes that help to protect lung tissues from infection and damage. Conversely, SPDEF activated genes that promote inflammation and excessive mucus, in particular, forkhead box A3, anterior gradient 2 and mucins.

Identifying the genetic circuits that cause mucus hyperproduction gives researchers potential targets for new therapies to moderate or stop it. The current researchers plan to conduct more extensive studies into the various genetic and molecular influences that control, or are controlled by, SPDEF and are involved in excess mucus production.
Scientists at the Cincinnati Children’s Hospital have identified the main genetic switch that causes excessive mucus in the lungs, a discovery that elucidates the biological reasons that the lungs in people with asthma, cystic fibrosis and other respiratory ailments become obstructed with thick mucus, which could lead to new therapeutic pathways. Scientists previously thought that after airways were attacked by an allergic response or inflammation, goblet cells divided and proliferated by hyperplasia. The current team discovered that in fact, Clara cells change their cell type to become goblet cells via metaplasia and found the 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. The study, details of which were published in the 14th September online edition of the Journal of Clinical Investigation (10.1172/JCI39731), identified a transcription factor, SPDEF, as the master gene that regulates a chain of many downstream genes involved in mucus production.

SPDEF is actively involved 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. Using ovalbumin to induce an allergic reaction and inflammation in the lungs of mice, the investigators observed a dramatic elevation in SPDEF expression in the lung tissues of affected animals. The animals also experienced hyperproduction 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 a 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 reported that SPDEF turned off genes involved in biological processes that help to protect lung tissues from infection and damage. Conversely, SPDEF activated genes that promote inflammation and excessive mucus, in particular, forkhead box A3, anterior gradient 2 and mucins.

Identifying the genetic circuits that cause mucus hyperproduction gives researchers potential targets for new therapies to moderate or stop it. The current researchers plan to conduct more extensive studies into the various genetic and molecular influences that control, or are controlled by, SPDEF and are involved in excess mucus production.

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