Cystic fibrosis protein linked to emphysema

A research team from the Hopkins Children’s Center recently discovered that the protein defective in people with cystic fibrosis also helps to regulate inflammation and cell death in emphysema.

These findings may help facilitate treatments for lung diseases caused by infections or cigarette smoke in emphysema.

The protein CFTR (cystic fibrosis transmembrane conductance regulator) is an ion channel that helps transport chloride ions across epithelial cell membranes. Cystic fibrosis, a genetic disease that causes abnormally thick mucus to accumulate in the lungs and pancreas, is caused by mutations in this protein. The disease can result in respiratory problems and increased risk of lung infection, among other symptoms.

The study, led by Neeraj Vij, found that CFTR affected a wider range of immune regulation and response than previously believed.

By comparing lung tissue from people with and without emphysema, the team found a close relationship between the level of functioning CFTR and the severity of the disease, with the more emphysema-damaged lung tissue having less CFTR on the cell surfaces.

The decrease in CFTR also corresponded with an increased buildup of ceramide, a fatty molecule known to trigger inflammation and cell death, in the lungs.

According to Vij, whose lab works to identify molecular pathways that lead to functional changes in an organism as a result of chronic disease, these results suggest that CFTR regulates inflammation and cell death by preventing the over-accumulation of ceramide.

To better understand the role of cigarette smoking in causing emphysema, the researchers compared CFTR and ceramide levels from the lung tissues of non-smokers to light and heavy smokers or former smokers.

They also compared lung tissue from mice never exposed to smoke to that of mice exposed to cigarette smoke for five hours a day over five days.

The results supported those of the initial study and showed that cigarette smoke indeed results in lung damage, as the lungs of the mice had both increased ceramide and decreased CFTR levels.

In humans, the same trend was observed in smokers, with heavier smokers having higher ceramide and lower CFTR levels.

The team also examined the role of CFTR in causing ceramide-triggered inflammation. By analyzing lung cells from CFTR-deficient people and mice using a flow cytometer, an instrument that records changes in inflammatory and protein markers, the team noticed increased ceramide clustering on lipid rafts.

Lipid rafts are sections of the cell membrane where inflammatory signaling proteins are known to concentrate.

As no such clustering was observed in cells with normal CFTR, the researchers believe that CFTR usually regulates inflammatory receptor signaling by preventing ceramide clustering.

Vij believes that ceramide and CFTR could be useful predictors of susceptibility to smoke-induced lung damage. Therefore, treatments that target CFTR-dependent lipid rafts will be more effective in treating chronic lung disease.

The last part of the study uses ceramide inhibitors to treat bacteria-caused lung damage in mice. One inhibitor, FB1, decreased ceramide buildup in mice with intact CFTR but could not do the same for CFTR-absent mice, indicative of CF.

The other, AMT, mediated ceramide activity in mice with absent CFTR, but not those with decreased CFTR, indicative of emphysema. These results suggest that different therapies will have to be used to treat lung damage caused by emphysema and CF.