Gene linked to mucus production hints at treatment for cystic fibrosis

Scientists in the US have found a genetic switch that effects excess mucus production in lung diseases such as asthma and cystic fibrosis (CF), and even the common cold.

Healthy lungs help remove contaminants and defend the body by producing mucus - a sugar-coated collection of large proteins. The lungs of people with respiratory illnesses, however, clog with thick excess mucus, the reason for which is unknown. Identifying the cause of this 'mucus hyperproduction' could lead to new therapies to prevent or stop it, says Dr Jeffrey Whitsett, the head of Neonatology, Perinatal and Pulmonary Biology at Cincinnati Children's Hospital Medical Center, and senior investigator of the research. He explained: 'We still don't have effective therapies for removing excess mucus, 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'.

It was previously thought that mucus cells called goblet cells multiply and proliferate in a process called hyperplasia as a result of an allergic or inflammatory response, and hyperproduce mucus. This current study, however, shows that beneficial lung cells called Clara cells change their cell type to become goblet cells in a process called metaplasia, which is controlled by a specific genetic switch, and cause mucus hyperproduction. Metaplasia was also found to be reversible in this instance; goblet cells can change back into Clara cells if the genetic switch is blocked. This therefore may provide a pathway for potential therapies.

The work identified a gene called SPDEF that is involved in normal mucus production in healthy organs, although it is mostly quiet in healthy lungs as they do not produce much mucus. After an inflammatory response was activated in mice using ovalbumin protein to produce an allergic reaction, SPDEF expression was increased dramatically in lung tissue, and the mice had hyper-production of thick mucus in the lungs. When the SPDEF gene was switched off in mice, there was no inflammatory response or excess mucus production in the lungs. Mice lacking SPDEF were also unable to produce goblet cells or excess mucus. Some genes downstream of SPDEF that promote inflammation and excess mucus production were also identified, in particular FOXA3, AGR2 and mucins.

Whitsett and his colleagues hope for therapies for hyperproduction of mucus, but warn that it will be several years before any treatments that may be developed can be tested in humans. Dr Keith Prowse, spokesperson for the British Lung Foundation, told the BBC: 'Excess mucus production blights the lives of millions of patients with chronic lung conditions such as cystic fibrosis and chronic obstructive pulmonary disease', and added that 'the finding that SPDEF which controls mucus production could lead to new and effective treatments which would benefit' millions of people in the UK.