Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology.

BACKGROUND: The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear. OBJECTIVES: We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19. METHODS: We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection. RESULTS: We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage. CONCLUSION: These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.

SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

Emergência hipertensiva e acidente vascular cerebral isquêmicoe hemorrágico: conceitos atuais de tratamento / Hypertensive emergency and ischemic and hemorrhagic stroke: current concepts of treatment

Esta revisão descreve a epidemiologia da doença cardiovascular e de seus fatores de risco em países desenvolvidos e em desenvolvimento. Ela discute que estudos epidemiológicos observacionais e prospectivos de base populacional mostram uma contínua e positiva associação entre pressão arterial e o risco de acidente vascular encefálico ou outros eventos vasculares. Assim, esta revisão caracteriza a elevação aguda da pressão arterial e o comprometimento de órgãos-alvo como emergência hipertensiva e mostra o acidente vascular encefálico isquêmico e hemorrágico como manifestação da emergência hipertensiva. Por fim, examina conceitos atuais sobre tratamento de ambas as apresentações do acidente vascular encefálico durante a emergência hipertensiva.

This review describes the epidemiology of cardiovascular disease and of its risk factors in developed and in developing countries. It discusses that epidemiologic prospective population-based observational studies have shown a continuous and positive relationship between blood pressure and the risk of stroke or other major vascular events. Thus, it features the acute elevation of blood pressure and the target-organ damage as a hypertensive emergency, and shows the ischemic and hemorrhagic stroke as a manifestation of hypertensive emergency. Finally, it examines current concepts of treatment of both presentations of stroke during hypertensive emergency.