A new treatment is among the first known to reduce the severity of acute respiratory distress syndrome caused by influenza in animals, according to a new study.
Tests in mice infected with high doses of influenza have shown that the treatment can improve lung function in very sick mice and prevent disease progression in mice treated preventively after exposure to influenza.
The hope is that it may also help humans infected with the flu and potentially other causes of acute respiratory distress syndrome (ARDS) like SARS-CoV-2 infection.
Specific cells in mice are less able to make key molecules after the flu has invaded the lungs, which reduces their ability to produce a substance called surfactant that allows the lungs to expand and contract. The surfactant shortage is linked to ARDS, a condition so severe that it usually requires mechanical ventilation in an intensive care unit.
The researchers bypassed the blocked process in mice by reintroducing the missing molecules alone or in combination as an injected or oral treatment. The results: normalized blood oxygen levels and reduced inflammation in the lungs of mice – effects that could make a person well enough to be discharged from hospital.
“The biggest and most impressive thing about this study is the fact that we have benefits even when we are dealing late in the disease process. If we could develop a drug based on these results, you could take someone who is going to need a ventilator and stop this altogether, ”said Ian Davis, professor of veterinary biosciences at Ohio State University and lead author. of the study. “There is nothing out there now that can do that for ARDS that will bring them back to this level, and certainly not for the flu.
ARDS can also result from infections, cancer, trauma, and many other conditions. Although this therapy has been tested against the background of influenza, Davis said her reliance on fixing broken cell function in the host rather than killing the virus suggests it has the potential to treat virtually all lung damage.
The study was published online recently in the American Journal of Respiratory Cell and Molecular Biology.
The experimental treatment consists of molecules called liponucleotides, which are essential for making a surfactant in the lungs. Davis analyzed lung cells from influenza-infected mice and determined that the surfactant production pathway was interrupted, with one of the two required liponucleotides being completely undetectable.
“The thought before was that the reason there was less surfactant in mice with influenza-related ARDS was because the cells were dying. problem with cell metabolism, maybe you can fix it, ”Davis said.
And correct it – in mice – it did, by developing therapies containing the missing liponucleotide molecule alone or in combination with one or two others.
Davis and his colleagues inoculated mice with high doses of H1N1 influenza, then treated some mice with liponucleotides once daily for five days and others only once five days after exposure. Mice given daily treatment were protected against serious disease, and very sick mice treated on day 5, whose severe loss of blood oxygen and lung inflammation caused ARDS, showed significant improvement.
“Obviously that’s what you need in a person with severe flu – we want to take someone who’s already in the intensive care unit and help them get out faster, or head to it. cervical intensive care unit, ”Davis said.
Liponucleotides don’t kill the flu virus – which is the point.
“I have always been interested in finding new therapies to treat lung damage,” he said. “The problem with antiviral drugs is that you probably need a different drug for each virus. In addition, many viruses can mutate quickly to become resistant to these drugs.
“Our approach is to treat the patient. Once the virus has caused the injury – the inflammation – it doesn’t matter whether it stays or goes away.”
There is still a lot to learn. The agents have a potent anti-inflammatory effect, but don’t completely restore the surfactant production process – and Davis isn’t sure why. Studies so far have been based on findings in a single type of lung cell, but scientists have not confirmed that these cells are the ones that respond to therapy – any number of other cells in the system. immune system, blood vessels or the heart also play a role.
Despite the unknowns, Davis said that because the missing liponucleotides exist naturally in mammals, including humans, they are considered safe and unlikely to cause side effects, even if not used in the body. .
The Ohio State Innovation Foundation has filed for patents covering the scope of Davis’ findings, which may also extend to patients with other forms of lung damage that cause inflammation and lower oxygen levels in the blood.
This work was supported by the National Heart Lung and Blood Institute.
Co-authors include Lucia Rosas, Lauren Doolittle, Lisa Joseph, Hasan El-Musa, and Judy Hickman-Davis of the Ohio State College of Veterinary Medicine; Michael Novotny of the Cleveland Clinic; and Duncan Hite of the University of Cincinnati.