Antidepressant Reduces Cell Death and Lung Infections in CF Mice Model

Nature Medicine recently published a study that looked at some of the effects from defective CFTR proteins in mice. The researchers were attempting to find more specific reasons why defective CFTR proteins cause thick mucus and increased infection. They studied mouse models of cystic fibrosis, specifically looking at a lipid that regulates cell death and inflammation. By using a drug that is used as an antidepressant to block this lipid, they found a reduction in lung infection in the mice.

The study found that cells lacking the CFTR protein had abnormally high pH levels (about 5.9 or higher) due to the imbalance of ions passing through the cell membrane. One of the effects of this pH difference was to alter the activity of several enzymes that rely on more acidic levels (pH around 4.5) in normal cell lysosomes to regulate metabolism of a lipid called ceramide. Ceramide is involved in the regulation of cell survival and the expression of proinflammatory cytokines. When the pH level inside the cell is too high, it reverses one of the enzymes that degrades ceramide so that it actually produces more ceramide. This causes a net increase in cellular ceramide levels, which then causes increased cell death and inflammatory response.

The increase in cell death results in fragments of DNA throughout in the lungs of the mice that were tested. These DNA fragments cause the mucus in the lungs to become more clogged and sticky. Additionally, the bacterium that causes many lung infections in CF patients, P. aeruginosa, thrives by attaching to these DNA fragments. Then, because of the infection that is present, the body responds by producing more ceramide with attempts to destroy the bacteria. This leads to a vicious cycle in CF patients, where further increases in ceramide levels cause further cell death, DNA fragments, P. aeruginosa adhesion, and inflammation. All these things lead to an increase in viscoelasticity of airway mucus - in other words, the mucus becomes stickier, and causes impaired clearance of the bacteria. This allows the infections to flourish: while normal mice started fighting off the P. aeruginosa so that levels decreased, the levels of P. aeruginosa in the CF mice increased exponentially.

The researchers used a drug called Amitriptyline that functions to decrease the actions of the enzyme that is mistakenly producing ceramide levels in the cells with a high pH. It also targets a second enzyme that functions to produce ceramide. They found a significant decrease in ceramide levels in the CF mice treated with the drug. This resulted in a decrease in infections seen in these mice.

This study shows a potential treatment that may help prevent or delay the onset of lung symptoms for patients with CF. It also could reduce existing pulmonary infections for CF patients who have already contracted P. aeruginosa. The researchers note the importance of finding an exact amount of the drug to use, because decreasing ceramide by too much would impair the ability of cells to fight infection. It could be tricky to find the correct dosage to regulate ceramide levels. However, this drug definitely has potential for a new treatment of CF. One advantage is that the drug has already been approved by the FDA for use as an antidepressant. With further research, this drug may be very useful to help CF patients fight lung infections and thin out mucus to normal levels.

Reference: Teichgraber et al. 2008. Ceramide accumulation mediates inflammation, cell death, and infection susceptibility in cystic fibrosis. Nature Medicine 14: 382:391.