A US Food & Drug Administration (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 causing immune-mediated damage to the lungs, according to a preclinical study from Weill Cornell Medicine and Cold Spring Harbor Laboratory researchers.
The team 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 TRALI, that in rare cases, occurs after blood transfusion.
“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 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.
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 (oedema) and promoting the development of blood clots. Disulfiram blocks one of the steps in NETs formation.
The study was a collaboration between Schwartz’s research group and a group led by Dr Mikala Egeblad, professor and cancer centre co-leader at Cold Spring Harbor Laboratory, and was published in JCI Insight.
Disulfiram, a compound originally used in the production of rubber, 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 drinking problems.
Scientists found in 2020 that disulfiram also inhibits part of the inflammatory process that can lead to NET formation by white blood cells called 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 with 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 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.
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,” Schwartz said.
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 favourable 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.
“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,” Schwartz said. Other researchers have begun small clinical trials of disulfiram in COVID-19 patients, although the results of those trials have not yet been published, he noted.
Study details
Disulfiram inhibits neutrophil extracellular trap formation protecting rodents from acute lung injury and SARS-CoV-2 infection.
Jose Adrover, Lucia Carrau, Juliane Daßler-Plenker, Yaron Bram, Vasuretha Chandar, Sean Houghton, David Redmond, Joseph Merrill, Margaret Shevik, Benjamin R. tenOever, Scott Lyons, Robert Schwartz, Mikala Egeblad.
Published in JCI Insight on 8 February 2022.
Abstract
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. 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 transfusion-related acute lung injury (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 down-regulated 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.
Study details
Targeting potential drivers of COVID-19: Neutrophil extracellular traps
Betsy Barnes, Jose Adrover, Amelia Baxter-Stoltzfus, Alain Borczuk, Jonathan Cools-Lartigue, James Crawford, Juliane Daßler-Plenker, Philippe Guerci, Caroline Huynh, Jason S. Knight, Massimo Loda, Mark Looney, Florencia McAllister, Roni Rayes, Stephane Renaud, Simon Rousseau, Steven Salvatore, Robert Schwartz, Jonathan Spicer, Christian C. Yost, Andrew Weber, Yu Zuo, Mikala Egeblad.
Published in Journal of Experimental Medicine on 2020;
Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
JEM article – Targeting potential drivers of COVID-19: Neutrophil extracellular traps (Open access)
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Alcohol problems severely undertreated in US – University of Washington
Increased risk of death and serious illness among COVID-19 survivors
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