Cystic Fibrosis Progression Traced to Acidity in Airway Liquid

University of Iowa researchers appear to have discovered the long-awaited answer as to why mice that carry cystic fibrosis (CF) mutations do not develop the serious lung disease observed in human CF patients. Their work also revealed a new therapeutic target that might stop CF progression. The study, “Airway acidification initiates host defense abnormalities in cystic fibrosis mice,” was published in the journal Science.

Previous university research using pig models of CF showed that the level of acidity in the thin layer of liquid covering the airways is extremely important in protecting against infections. CF pigs have unusually acidic airway liquid, and this high acidity impairs their ability to fight off infection in the airways and lungs.

Airway acidity is normally controlled by two opposing factors. The cystic fibrosis transmembrane conductance regulator (CFTR, a gene that is mutated in CF patients) channel secretes bicarbonate, a base, and protons secrete a counterbalancing acid to establish an equilibrium. When people, mice and pigs develop CF, the bicarbonate flow stops, and the airways become much more acidic. In pigs and people this decreases the ability to fight infection and frequently causes lung disease, but in mice the liquid acidity and susceptibility to infection are not observed.

Scientists for this reason compared airway tissue from mice, humans and pigs, and found that a proton pump, called ATP12A, is responsible for this effect. Blocking this pump in the airway tissue of humans and pigs led to a decrease in acidity and restoration of the defense mechanisms against infection. Putting the proton pump into airways of CF mice, where ATP12A expression naturally is low, increased the acidity and lead to a mouse predisposition to bacterial infections.

As the ATP12A proton pump is independent of CFTR, the researchers believe that targeting the pump may be helpful for all types of CF.

“This discovery helps us understand the cause of lung disease in people with CF. It may also identify ATP12A as a new therapeutic target,” Viral Shah, a student at the UI Carver College of Medicine and the study’s first author, said in a press release. “We wonder if blocking ATP12A in people with CF could halt the progression of lung disease.”