Autor(es):
Silva, Camila Meirelles S. ; Wanderley, Carlos Wagner S. ; Veras, Flavio P. ; Sonego, Fabiane ; Nascimento, Daniele C. ; Gonçalves, Augusto V. ; Martins, Timna V. ; Cólon, David F. ; Borges, Vanessa F. ; Brauer, Verônica S. ; Damasceno, Luis Eduardo A. ; Silva, Katiussia P. [UNESP] ; Toller-Kawahisa, Juliana E. ; Batah, Sabrina S. ; Souza, Ana Letícia J. ; Monteiro, Valter S. ; Oliveira, Antônio Edson R. ; Donate, Paula B. ; Zoppi, Daniel ; Borges, Marcos C. ; Almeida, Fausto ; Nakaya, Helder I. ; Fabro, Alexandre T. ; Cunha, Thiago M. ; Alves-Filho, José Carlos ; Zamboni, Dario S. ; Cunha, Fernando Q.
Data: 2022
Identificador Persistente: http://hdl.handle.net/11449/231550
Origem: Oasisbr
Descrição
Made available in DSpace on 2022-04-29T08:46:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-23
Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.
Center for Research in Inflammatory Diseases
Department of Biochemistry and Immunology
Department of Pharmacology
Department of Cellular and Molecular Biology and Pathogenic Bioagents Ribeirao Preto Medical School University of Sao Paulo, Ribeirao Preto
Institute of Biosciences Sao Paulo State University, Botucatu
Pathology and Legal Medicine
Department of Internal Medicine Ribeirao Preto Medical School University of Sao Paulo, Ribeirao Preto
Hospital Israelita Albert Einstein Sao Paulo
Institute of Biosciences Sao Paulo State University, Botucatu
