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

Jose M Adrover,Vasuretha Chandar,Joseph R Merrill,Scott K Lyons,Lucia Carrau,Juliane Daßler-Plenker,Margaret Shevik,David Redmond,Sean Houghton,Benjamin R Tenoever,Robert E Schwartz,Yaron Bram,Mikala Egeblad

doi:10.1172/jci.insight.157342

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 it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.

Highlights

Acute respiratory distress syndrome (ARDS) has a high in-hospital mortality rate that increases significantly with age [1]
Disulfiram efficiently blocked PMA-induced neutrophil extracellular traps (NETs) formation using neutrophils purified from mouse blood (Figure 1A) or human peripheral blood (Figure 1B), and it blocked NET formation in a dose-dependent manner (Supplemental Figure 1B)
IFNs are key for antiviral immunity, including against SARS-CoV-2 [53, 54], and we found increased IFN signaling genes and IFN regulatory factors in the disulfiram-treated lungs compared with the vehicle-treated controls (Supplemental Figure 4, D and E), indicating that IFN responses are not reduced by disulfiram-mediated NET inhibition

Summary

Introduction

Acute respiratory distress syndrome (ARDS) has a high in-hospital mortality rate that increases significantly with age [1]. Excessive formation of neutrophil extracellular traps (NETs) is increasingly being recognized as a key contributor to acute lung injury (ALI) or ARDS [2–4]. NETs can be formed in response to tissue damage or viral infections [7–13]. NET formation can help contain infections, it can inflict severe damage to the host tissue [4, 14, 16]. Excessive NET formation can directly damage the lung microvasculature [17–20] and promote thrombosis [21–23], leading to multiorgan damage and cardiovascular complications [24]. Microvascular damage, thrombosis, and cardiovascular complications are known complications of severe COVID-19 [25]. Elevated levels of NETs are found in the blood, thrombi, and lungs of patients with severe COVID-19 [21, 26–28], suggesting that neutrophils and NETs may play an important role after infection with SARS-CoV-2

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