New research suggests that a drug already approved for the treatment of metabolic acidosis – where the body has too much acid – could be repurposed and used to treat airway disease in patients with cystic fibrosis. The drug showed enhanced ability to kill bacteria in the airways of pigs and mucus samples from human patients with cystic fibrosis.
Joseph Zabner, a professor of internal medicine, together with other researchers from the University of Iowa Carver College of Medicine in Iowa City describe their findings in a paper published in the journal JCI Insight.
Cystic fibrosis (CF) is a progressive, genetic disease that damages the internal organs, especially the lungs and the gut. In people with CF, a faulty gene called CFTR causes a build-up of thick mucus on the surfaces of tissue – for example the lining of airways and the digestive tract.
In the lungs, as the mucus accumulates, it clogs up the airways, causing breathing problems. It also traps bacteria and gives rise to infections, extensive lung damage, and eventually respiratory failure.
The mucus build-up is a result of a problem with transporting ions in and out of cells, which causes the affected tissue surfaces to become too acidic.
In the lungs, if the airway surface liquid (ASL) becomes too acidic, it is less able to defend against bacteria and other pathogens.
For their study, the researchers investigated the effect of a drug called tromethamine (which they refer to as Tham) on the acidity of the ASL and its ability to kill bacteria.
In the United States, Tham is currently approved – in injectable form – as a treatment for metabolic acidosis, a condition where the body either becomes too acidic or the kidneys are not able to remove enough acid from the body.
First, the team confirmed that one way to reduce the acidity of the ASL is to inhale aerosolized bicarbonate (HCO3-), which does reduce the acidity of the ASL, but the effect only lasts for about 30 minutes.
- In the U.S., there are over 33,000 people living with CF
- More than 75 percent of people with CF are diagnosed by the age of 2
- People with CF have inherited two copies of the defective gene.
They then showed that an aerosolized version of Tham was able to reduce acidity – that is raise pH – of the ASL in both pigs and humans with CF.
Just as important, they found Tham boosted bacterial killing in the airways of pigs with CF and in sputum samples from human patients.
“We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing,” note the authors.
The researchers also tested the effect of administering tromethamine with salt solution – hypertonic saline.
Salt solution is known to help clear mucus from airways and decrease the frequency of CF flare-ups. But there is a potential drawback – previous research by Zabner’s team and others shows that salt can block individual and collective antimicrobial effects of a group of molecules called peptides.
However, the researchers found that tromethamine “increases sputum pH and improves bacterial killing even in the presence of hypertonic saline.”
“We speculate that perhaps a combination of Tham and hypertonic saline might be of therapeutic benefit in CF airways.”
Prof. Joseph Zabner and colleagues