An FDA-approved drug that has been in clinical use for more than 70 years may protect against lung injury and the risk of blood clots in severe COVID-19 and other disorders that cause immune-mediated damage to the lungs, according to a preclinical study from scientists at Weill Cornell Medicine and Cold Spring Harbor Laboratory.
The researchers, whose study (“Disulfiram inhibits neutrophil extracellular trap formation protecting rodents from acute lung injury and SARS-CoV-2 infection”) appears in JCI Insight, found that the drug disulfiram protected rodents from immune-mediated lung injury in two separate models of this type of injury: infection with the SARS-CoV-2 coronavirus that causes COVID-19, and a lung failure syndrome called transfusion-related acute lung injury (TRALI) that in rare cases occurs after blood transfusion.
“Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development,” the investigators wrote.
“Here, we report that disulfiram—an FDA-approved drug for alcohol use disorder—dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a TRALI mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for COVID-19 patients.
“In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in two rodent models of lung injury for which treatment options are limited.”
“As we learn more about the underlying biology of these lung injuries, we may be able to specifically target the processes that are damaging the lung tissue,” said senior co-author Robert Schwartz, MD, PhD, an associate professor of medicine in the division of gastroenterology and hepatology at Weill Cornell Medicine and a hepatologist at New York-Presbyterian Hospital/Weill Cornell Medical Center.
Immune cells’ formation of web-like structures
Both types of lung injury are now known to be driven in part by immune cells’ formation of web-like structures called NETs. These can trap and kill infectious organisms, but can also be harmful to lung tissue and blood vessels, causing the accumulation of fluid in the lungs (edema) and promoting the development of blood clots. Disulfiram blocks one of the steps in NETs formation.
Disulfiram exhibits an interesting history almost from its start as a medicine. The compound was originally used in the production of rubber, and was later investigated as an anti-parasite treatment. Incidental observations that people taking it became mildly sick whenever they drank alcohol led to its FDA approval in 1951 as a deterrent to alcohol consumption for people with alcohol use disorder.
Scientists found in 2020 that disulfiram also inhibits part of the inflammatory process that can lead to NET formation by neutrophils. The finding prompted the testing of disulfiram as a NET blocker. “NETs will damage the tissue, but since disulfiram interferes with gasdermin D, a molecule needed to produce NETs, no NETs are formed after disulfiram treatment,” Egeblad said.
After confirming in lab-dish experiments that disulfiram does greatly reduce the formation of NETs by human and mouse neutrophils, the researchers tested it in models of TRALI and COVID-19, two diseases that are known to feature extensive neutrophil invasion of the lungs, NET formation, and often fatal lung damage.
In a mouse model of TRALI, disulfiram treatment a day before and then again three hours before induction of the syndrome allowed 95% of the animals to survive, compared to just 40% of those not treated with the drug. The findings showed that disulfiram, apparently by reducing NET formation, blocked the progressive damage to lung tissue and vessels that occurred in untreated mice, and in so doing allowed lung function to stabilize and recover relatively quickly after initial damage.
By contrast, an inhaled drug called DNase 1, which has been investigated as a potential TRALI treatment, had no significant effect in improving the mouse survival rate even when administered minutes before TRALI induction.
In earlier collaborative work published in the Journal of Experimental Medicine, autopsy results suggested that NETs were present in severe COVID-19 patients and raised a novel possibility.
“Currently there aren’t any good treatment options for COVID-related lung injury, so disulfiram appears to be worth investigating further in this regard, particularly in severe COVID-19 patients,” noted Schwartz.
Next, the researchers tested disulfiram in a golden hamster model of COVID-19. This form of COVID-19 is less severe than what is seen in the worst human cases, but disulfiram treatment a day before or a day after infection with SARS-CoV-2 led to clearly favorable outcomes: less NET formation, less fibrosis in the lungs, and gene activity changes suggesting a significant reduction in the harmful inflammatory response without impairment of antiviral immunity.
By comparison, the standard severe-COVID-19 treatment dexamethasone, an immune-suppressing steroid drug, did less to protect lung tissue from disease-related changes, and led to higher levels of SARS-CoV-2 in the lungs.
“Disulfiram’s strong inhibitory effect on NET formation and its improvement of disease outcomes in different rodent models highlight the potential for its use and for the future development of even better inhibitors of NET formation in a variety of diseases,” said Schwartz.
Other researchers have begun small clinical trials of disulfiram in COVID-19 patients, although the results of those trials have not yet been published.
