The old drug may protect against COVID-19 lung damage, the study notes
Pneumonia and lung injury was the cause of many deaths in the second wave of COVID-19. Doctors everywhere tried their best to find a cure that cured pneumonia. Now, a new preclinical study by researchers at Weill Cornell Medical and Cold Spring Harbor Laboratory has shown a ray of hope.
They say the FDA-approved drug, which has been in clinical use for more than 70 years, can protect against lung damage and the risk of blood clots in COVID-19 and other diseases that cause immune-mediated lung damage. The results of their research were published in “JCI Insight”.
The study found that disulfiram protected rodents from immune-mediated lung damage in two distinct models of this type of injury: infection with the SARS-CoV-2 coronavirus, which causes COVID-19, and a lung syndrome called TRALI, which is rare. cases occur after a blood transfusion.
“As we learn more about the biology behind these lung injuries, we may be able to specifically target processes that damage lung tissue,” said senior co-author Dr. Robert SchwartzAssistant Professor of Medicine at Weill Cornell Department of Medical Gastroenterology and Hepatology and Hepatologist at New York Presbyterian Hospital / Weill Cornell Medical Center.
Both lung lesions are now known to be due in part to the formation of network-like structures by immune cells called extracellular traps or NETs of neutrophils. They can trap and kill infectious organisms, but can also be harmful to lung tissue and blood vessels, causing fluid to build up in the lungs (swelling) and promoting the formation of blood clots. Disulfiram inhibits one of the steps in NET formation.
The study was conducted in collaboration with Dr. Schwartz’s research team and Dr Mikala Egebladprofessor and second director of the Cancer Center at Cold Spring Harbor Laboratory.
Serendipity has been attached to disulfiram almost since the beginning of its history. The compound was initially used in the manufacture of rubber and was later studied as an antiparasitic treatment. The occasional finding that people who used it became mildly ill whenever they drank alcohol led to its FDA approval in 1951 to prevent alcohol use in people with alcohol use disorders.
In 2020, researchers found that disulfiram also blocks part of the inflammatory process that can lead to the formation of NET by white blood cells called neutrophils. The discovery led to the testing of disulfiram as a NET inhibitor. “NETs damage tissue, but because disulfiram interferes with gasdermin D, the molecule needed to produce NETs, NETs are not formed after disulfiram treatment,” Dr. Egeblad said.
After confirming in laboratory experiments that disulfiram significantly reduces the formation of NET in human and mouse neutrophils, the researchers tested it in the TRALI and COVID-19 models, two diseases known to have extensive neutrophil infiltration into the lung, NET. formation and often fatal lung damage.
In a mouse model of TRALI, treatment with disulfiram the day before the syndrome induction and then again three hours before the syndrome induction allowed 95% of the animals to survive, compared with only 40% of those not treated with the drug. The findings showed that disulfiram, apparently by reducing NET formation, prevented progressive damage to lung tissue and blood vessels in untreated mice, thus allowing lung function to stabilize and recover relatively quickly after the initial injury.
In contrast, an inhaled drug called DNase 1, which has been studied as a possible TRALI treatment, had no significant effect on improving the survival rate of mice even when administered one minute before TRALI induction.
In a collaboration previously published in the Journal of Experimental Medicine, autopsy results suggested the presence of NETs in severe COVID-19 patients and highlighted a new possibility.
“There are currently no good treatment options for COVID-derived lung injury, so disulfiram appears to be worth further investigation in this regard, especially in severe COVID-19 patients,” Dr. Schwartz said.
Next, the researchers tested disulfiram in a golden hamster model of COVID-19. This form of COVID-19 was milder than that observed in the worst humans, but treatment with disulfiram the day before or the day after SARS-CoV-2 infection resulted in clearly favorable results: less NET formation, less scar-like. tissue formation (fibrosis) in the lungs and changes in gene activity that suggest a significant reduction in the harmful inflammatory response without a decrease in antiviral immunity.
In comparison, standard severe COVID-19 treatment with dexamethasone, an immunosuppressive steroid, protected less lung tissue from disease-related changes and resulted in higher levels of SARS-CoV-2 in the lung.
“The strong inhibitory effect of disulfiram on NET formation and the improvement in its disease outcomes in different rodent models highlight the potential for its use and the development of better net inhibitors of NET formation in several diseases in the future,” Dr. Schwartz said. Other researchers have initiated small clinical trials of disulfiram in COVID-19 patients, although the results of these studies have not yet been published, he noted.
Source: ANI