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Neutrophil extracelular traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID-19

Grant number: 20/07645-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2020
Effective date (End): April 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Fernando de Queiroz Cunha
Grantee:Flávio Protásio Veras
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:20/05601-6 - Neutrophil extracelular traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID-19, AP.R

Abstract

The disease caused by coronavirus in 2019 (Covid-19) is caused by coronavirus-2 of severe acute respiratory syndrome (SARS-CoV-2) and has become an important health problem worldwide. The pulmonary changes observed in patients with Covid-19 are characterized by intense damage to epithelial and endothelial cells, viral replication in pulmonary tissue and extensive inflammatory process characterized by edema, infiltration of inflammatory cells, including neutrophils and increased tissue concentrations of inflammatory cytokines , such as TNF-±, IL-1 and IL-6. In addition to pulmonary changes, there is also a systemic inflammatory response with important lesions in other organs such as kidneys, heart and intestines. Recent studies suggest that neutrophils participate in lung injuries and possibly in other organs, but it is not yet clear what mechanisms are involved. Among the cytotoxic mediators released by this cell type are free radicals, enzymes and NETs (from Neutrophil Extracellular Traps) or, simply, extracellular traps of neutrophils, which are networks of DNA conjugated with antimicrobial enzymes such as myeloperoxidase (MPO), elastase and citrullinated histones. NETs are described as one of the main mediators responsible for injuries seen in several autoimmune diseases and also in vital organs during sepsis. However, the involvement of NETs in the injuries observed at Covid-19 remains unknown. Therefore, the objective of the present project is to identify the participation of NETs in the pathogenesis of Covid-19. The possible involvement of NETs in the pathogenesis of Covid-19 will allow us to propose new therapeutic approaches for this disease, that is, drugs that degrade this mediator and / or inhibit its synthesis. In this sense, we are also proposing to conduct an open clinical trial treating patients with Covid-19 with Pulmozyme. Pulmozyme is used in the clinic to treat cystic fibrosis and its active ingredient is DNAs that degrade NETs. Confirming the feasibility of the project, in a preliminary experiment, we observed an exacerbated production of NETs by isolated neutrophils and in the plasma of patients affected with Covid-19. (AU)