Drug for treating alcohol addiction may cure COVID-induced lung injury: Study

Disulfiram, a drug used to treat alcohol addiction, may protect against lung injury and the risk of blood clots in severe COVID-19, showed research published in the Journal of Clinical Investigation (JCI) insights, a peer-reviewed scientific publication .
 
Disulfiram has been in clinical use for more than 70 years across the world. According to a preclinical study from researchers at Weill Cornell Medicine and Cold Spring Harbor Laboratory, the drug 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 TRALI that in rare cases occurs after blood transfusion.
 
Both types of lung injury are now known to be driven in part by immune cells’ formation of web-like structures called neutrophil extracellular traps, or 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. “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,” said Dr. Mikala Egeblad, professor and cancer center co-leader at Cold Spring Harbor Laboratory.
 
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 per cent of the animals to survive, compared to just 40 per cent 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 stabilise 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.

“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,” said Dr. Robert Schwartz, an associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
 
The researchers also 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 scar-like tissue formation (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, the research showed.

“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,” Dr. Schwartz said.