“Drug ‘could aid cystic fibrosis’” is the headline on BBC News. The article says that “widely-used antidepressants could prevent infections which shorten the lives of many cystic fibrosis patients”.
The report is based on the findings from a study in mice which has shed further light on the biological processes involved in the changes to the lungs caused by the cystic fibrosis mutation. Lung infections are a major cause of death in people who have cystic fibrosis. Only further research will reveal whether these findings have direct relevance for humans. The antidepressant amitriptyline was not tested in humans here so, for now, this is not a treatment option for people with cystic fibrosis.
Where did the story come from?
Dr Volker Teichgräber and colleagues from the University of Southern California, the University of Duisburg-Essen, the Institute of Medical Microbiology and Hygiene in Germany, the University of Greifswald, and other academic and medical institutes across Germany carried out this research. The study was funded by grants from the Deutsche Forschungsgemeinschaft, Germany’s central public-funding organisation for academic research. It was published in Nature Medicine , a peer-reviewed medical journal.
What kind of scientific study was this?
This was a laboratory study, primarily conducted in mice, though there was an aspect of human-cell analysis. The researchers were trying to get a better understanding about the biological processes that take place in the lungs when an organism has cystic fibrosis. Cystic fibrosis is the most common inherited life-threatening disease that occurs among Caucasian people in the UK. In an experiment conducted in several different parts, the researchers used strains of mice with a mutation that gave them cystic fibrosis. They were particularly interested in the role of a particular lipid called ceramide.
In the first part of the experiment, the researchers compared the levels of ceramide in the lungs of the mutant mice with the levels in healthy mice. They did further experiments to identify in exactly which cells ceramide was accumulating. The researchers also looked at whether the ceramide concentration had any effect on pH (i.e. acidity) levels in the respiratory cells. The researchers were testing the theory that at the higher cell-pH associated with the cystic fibrosis mutation, the enzyme that normally breaks down ceramide does not work and sometimes produces more ceramide.
To see whether their findings were relevant to humans, the researchers compared the ceramide content in certain cells taken from the noses of 18 people with cystic fibrosis with nasal cells taken from 17 healthy controls. They also compared the ceramide content in lung samples from three people with cystic fibrosis who had had lung transplants (i.e. they compared the ceramide in their diseased lungs with ceramide in their healthy transplanted lungs).
To explore whether they could interrupt this disease-causing chain reaction, they injected some mutant mice with amitriptyline (a tricyclic antidepressant). They then examined whether treating the mice had an effect on the amount of bacteria in their lungs.
What were the results of the study?
The study was complex, with many different parts. These are the most relevant findings:
- There was a higher concentration of ceramide in the lungs of the mutant mice than those of healthy mice. This increase in concentration was linked to age. The accumulation of ceramide led to inflammation and other changes in the lung tissues (such as more dead cells and DNA deposits) that could increase susceptibility to infection.
- The pH of respiratory cells in mutant mice was increased. At this pH, the enzyme that should break down ceramide did not work and instead it manufactured more ceramide. When researchers prevented the activity of the enzyme in normal mice, they also saw an increase in the concentration of ceramide. This proved that the functioning of the enzyme is vital to reduce ceramide concentration.
- Injections of the drug amitriptyline led to a decrease in ceramide in the respiratory cells. The researchers found that mutant mice treated with amitriptyline had fewer bacteria (Pseudomonas aeruginosa , which commonly causes lung infection in people with cystic fibrosis) in their lungs and had reduced mortality from lung infection after seven days.
- In humans, there was significantly more ceramide in cells from nasal samples in people with cystic fibrosis compared with healthy controls. The researchers do not report the results of any comparison of human lung material.
What interpretations did the researchers draw from these results?
The researchers say that they have identified ceramide as a key regulator of “inflammation and subsequent infection in cystic fibrosis airways”. They add that the findings suggest that controlling the levels of ceramide by using amitriptyline may “represent a new and important strategy to prevent bacterial infections in people with cystic fibrosis”.
What does the NHS Knowledge Service make of this study?
The study is a well-conducted laboratory study. However, as it was carried out primarily in mice, the relevance of these findings for humans is unclear.
Cystic fibrosis is one of the most common hereditary diseases occurring in the UK. These findings will be of interest to the medical community as they provide additional insight into the possible pathology of this disease. Reporting that “experiments in mice have revealed how this happens” may incorrectly lead readers to believe that very little is currently know about the disease. The gene mutation in cystic fibrosis is well known to affect a cell membrane transporter of salt and water that leads to disease not only in the lungs, but also in other organs, such as the bowel and pancreas. In the lungs, abnormal movement of salt and water across the cell membrane leads to the production of abnormally thick and sticky mucus, which is more difficult for the lungs to clear. Accumulation of mucus is known to predispose to bacterial growth and infection. Current lung treatments for cystic fibrosis aim physically to shift the build up of mucus. Antibiotics are used to treat infections that occur.
At best, any technology based on these new findings is a long way off and more research is needed. Ceramide is a very important component of cells and regulating the amount of it will be extremely sensitive and difficult. The researchers themselves acknowledge that any treatment in humans will have to be very carefully controlled.
Sir Muir Gray adds...
It is always important to have an open mind; innovative approaches can come from unlikely sources.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
BBC News, 31 March 3008
Links to the science
Nature Med 2008; Mar 30 [Epub ahead of print]