CF mouse model reveals disease process

Marcus Mall, from the University of North Carolina in Chapel Hill, genetically modified mice to generate the typical symptoms of CF, something which has not been achieved to date. Prior research has revealed that mutations in the gene coding for the CF transmembrane regulatory (CFTR) in mice do not lead to CF symptoms.

Cystic fibrosis, also known as mucoviscidosis, is one of the most common genetic diseases with a fatal outcome in western Europe. The disease is caused by a defective gene that affects the salt and fluid composition of respiratory tract secretions. As a result, they become highly viscous. The viscous mucous then clumps in the smaller lung passages.

Using the new model, Mall has been able to demonstrate for the first time the long suspected relationship between the genetic defect, salt transport to the respiratory tract surface and the genesis of the lung disease in a living organism. This means that the origin of the disease and, possibly, types of therapy for humans can also be studied with these genetically modified mice.

To study the effect of the defective CFTR, Mall's group focussed on certain ion channels. These channels transport sodium ions through the cell membrane and thus regulate the fluid content of the cells. The altered fluid content of the mucous film that lubricates the respiratory tract causes clumping of the mucous so that natural removal of dust and bacteria from the respiratory tract is no longer possible.

Mice whose sodium ion channels had been altered became ill with the lung inflammation typical of cystic fibrosis. The researchers demonstrated with a high degree of probability the direct link between the ion transport disorder and CF.

"It has been unclear how the gene associated with cystic fibrosis, CFTR, which acts as a chloride channel and a regulator of the sodium channel, causes lung disease,"​ Mall said. "In particular, the relative importance of these two functions has been controversial and difficult to test. This mouse model demonstrated for the first time that accelerated transport of sodium ions alone is sufficient to cause this disease link through dehydration."​

Earlier work with genetically engineered mice had shown that neither malfunctioning cilia - the tiny airway hairs that beat in unison to clear mucus - nor over-secretion of mucus was enough to cause severe airway obstruction.

The genetically modified mice will be used by the researchers for further studies. The mice can be used to test how the illness originates, what other factors are involved and which medications or therapies may help. For example, drugs that improve hydration by blocking sodium channels or by increasing secretion of salt and water could counteract the symptoms of the disease. However, it remains unclear if all results are transferable to humans due to the difference in lung structure between mice and humans.

The results are published in the May edition of the journal Nature Medicine​.