Disulfiram inhibits neutrophil extracellular trap formation protecting rodents from acute lung injury and SARS-CoV-2 infection.

Adrover, Jose M, Carrau, Lucia, Daßler-Plenker, Juliane, Bram, Yaron, Chandar, Vasuretha, Houghton, Sean, Redmond, David, Merrill, Joseph R, Shevik, Margaret, tenOever, Benjamin R, Lyons, Scott K, Schwartz, Robert E, Egeblad, Mikala (February 2022) Disulfiram inhibits neutrophil extracellular trap formation protecting rodents from acute lung injury and SARS-CoV-2 infection. JCI Insight. ISSN 2379-3708

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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 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.

Item Type:	Paper
Subjects:	diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle > Neutrophil extracellular traps diseases & disorders > viral diseases organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > viral diseases > coronavirus diseases & disorders > viral diseases > coronavirus > covid 19 organs, tissues, organelles, cell types and functions > organs types and functions > lung organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent
CSHL Authors:	Merrill, Joseph Lyons, Scott Egeblad, Mikala Adrover, Jose M. DaBler-Plenker, Juliane Shevik, Margaret
Communities:	CSHL labs > Egeblad lab CSHL labs > Lyons lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Flow Cytometry Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	8 February 2022
Date Deposited:	23 Feb 2022 21:43
Last Modified:	09 Feb 2024 16:37
PMCID:	PMC8983145
URI:	https://repository.cshl.edu/id/eprint/40528

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