点击显示 收起
March 31, 2008 -- The antidepressantElavil prevents lung infection in mice with cystic fibrosis, but the dose must be exactly right to avoid harm.
The finding comes from researchers who may have found the key to why the genetic mutation that causes cystic fibrosis leads to the deadly lung-clogging infections that are the hallmark of the disease.
The cystic-fibrosis mutation disables a gene called CFTR (cystic fibrosis transmembrane conductance regulator). Researchers Erich Gulbins, MD, PhD, of Germany's University of Duisburg-Essen and colleagues now find that CFTR dysfunction upsets a delicate chemical balance in the lungs. This results in accumulation of a sticky lipid called ceramide.
As ceramide accumulates, it inflames the lung and kills lung cells. Debris from the dead cells piles up, giving a foothold to dangerous bacteria -- particularly the pseudomonas germs that plague people with cystic fibrosis.
Gulbins' team showed that this happens in mice lacking the CFTR gene. But they could prevent lung inflammation and pseudomonas infection by giving the animals Elavil.
Elavil is commonly used as an antidepressant. The drug works in cystic fibrosis by blocking an enzyme, Asm, that becomes overactive when CFTR isn't working properly.
"Treatment of CFTR-deficient mice with ... normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection," Gulbins and colleagues report. "Normalization of ceramide levels by may represent a new and important strategy to prevent bacterial infection in people with cystic fibrosis."
By blocking Asm, Elavil causes the body to make less ceramide. But Gulbins and colleagues warn that too little ceramide is dangerous. The sticky molecule helps remove bacteria from the airways. Mice with too little ceramide are unable to fight off lung infections.
"Thus any future cystic fibrosis drug targeting the Asm must be carefully titrated to normalize ceramide levels in the lungs of people with cystic fibrosis, but not reduce ceramide concentrations below a critical cellular level that would impair the biological functions of ceramide," they note.
Gulbins and colleagues report their findings in the March 30 online edition of Nature Medicine.