Researchers from Charité Universitätsmedizin Berlin discovered that cystic fibrosis medication may be useful in treating pneumonia after discovering the molecular pathways that cause fluid buildup in the lungs.
SARS-CoV-2 and pneumococcal pathogens can cause severe pneumonia. If the airways get clogged, the patient is in danger of developing acute respiratory distress syndrome. Researchers from Charité Universitätsmedizin Berlin found the molecular pathways that result in fluid buildup in the lungs and realized that Cystic fibrosis medications might help treat pneumonia.
In preclinical models, a medication for cystic fibrosis was successful, raising hopes that it could be used to treat pneumonia apart from the virus that caused it.
The findings were reported in Science Translational Medicine.
Pneumonia is the most prevalent cause of fluid accumulation in the lungs. This is known as pulmonary edema. It causes portions of the airspaces to fill with fluid instead of air, preventing them from fulfilling their duty of exchanging gases. A cystic fibrosis medicine showed success in laboratory tests. This boosted hopes that it may be used to treat pneumonia independently of the virus that caused it.
Patients have difficulty breathing, and their bodies are deficient in oxygen. The condition is known as acute respiratory distress syndrome (ARDS). Despite advanced medical techniques, around 40% of ARDS patients die in critical care.
The problem is that antibiotics, antivirals, and immune-modulating therapies rarely work well enough,” says study leader Prof. Dr. Wolfgang Kuebler, Director of the Institute of Physiology at Charité. “That’s why we took a very different approach in our study. Instead of focusing on the pathogen, we focused on strengthening the barrier function of the blood vessels in the lungs.”
This is understandable, given that they are the fluid source of pulmonary edema. The lung veins become porous, enabling blood fluid to leak into the surrounding tissue and, as a result, fill the airspace.
But what exactly is causing this? What are molecular processes at work?
Prof. Kuebler’s Charité research team set out to find answers to these problems.
Discovery of a possible new therapy
The team experimented with cells, lung tissue, and separate lungs.
The study focused on the CFTR chloride channel, mostly located in human airway mucosal cells. It is important to keep our mucus thin so it can drain readily. The researchers have now demonstrated for the first time that CFTR is present in cells in the lungs’ blood vessels and that its presence is greatly diminished in pneumonia.
The researchers used an inhibitor to block the channel. It controlled the number of chloride ions in the cells to determine what role CFTR performs in the pulmonary arteries and what happens at the molecular level when the chloride channel is destroyed. They then employed immunofluorescence imaging, a specialized imaging technique.
“We saw that inhibiting CFTR triggered a molecular cascade that ultimately causes the lung’s blood vessels to begin leaking,” says Dr. Lasti Erfinanda, who also works at the Institute of Physiology and is the study’s lead author. “So CFTR does play a very key role in the development of pulmonary edema.“
According to the findings of the study, the loss of CFTR causes chloride to accumulate in cells since it is no longer carried out of them. Excess chloride causes signaling, which results in an unregulated influx of calcium into cells via a calcium channel.
“The increased calcium concentration then causes the vascular cells to contract — much like the effect that calcium has on muscle cells,” explains Prof. Kuebler. “This results in gaps between the cells — which allows fluid to spill out of the blood vessels. Chloride channels are therefore crucial in maintaining the barrier function of the pulmonary vessels.”
The researchers then considered another question: how might they reduce or prevent the pneumonia-induced loss of chloride channels in the pulmonary vessels?
The researchers employed a medicinal drug known as a CFTR modulator. It is presently used to treat cystic fibrosis. A genetic mutation in cystic fibrosis patients inhibits the CFTR chloride channel from operating correctly in the mucosal cells of the airways. It results in highly viscous mucus.
“Ivacaftor is a drug that increases the chances of the chloride channel opening, which helps the mucus to flow through the airways,” says Dr. Erfinanda. “We wanted to see if it would also have a positive effect on the cells in the blood vessels of the lungs.”
Ivacaftor did make the chloride channels more stable. It induced less deterioration in the channels than is normally generated by inflammatory activities in the lung. Experiments on animal models revealed the same effect. Ivacaftor therapy doubled the likelihood of surviving severe pneumonia, decreased lung damage. It also resulted in considerably milder symptoms and a much better overall state than without the medication.
“We weren’t expecting it to function that well,” Prof. Kuebler explains. “We hope our findings will pave the way for clinical trials to test the efficacy of CFTR modulators in pneumonia patients. If this promising, pathogen-independent therapy finds its way into clinical practice, it could benefit a huge number of patients and prevent pneumonia from becoming life-threatening even in the case of unknown pathogens.”
Prof. Kuebler and his colleagues are now exploring new research initiatives.
It will be based on the CFTR signaling system to develop possible medicines. They will also investigate which individuals have an increased risk of having ARDS. This may help deliver preventative, customized therapy to these patients.