The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19

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de Carvalho, Jonatan C. S. ; da Silva-Neto, Pedro V. ; Toro, Diana M. ; Fuzo, Carlos A. ; Nardini, Viviani ; Pimentel, Vinicius E. ; Perez, Malena M. ; Fraga-Silva, Thais F. C. ; Oliveira, Camilla N. S. ; Degiovani, Augusto M. ; Ostini, Fatima M. ; Feitosa, Marley R. ; Parra, Rogerio S. ; da Rocha, Jose J. R. ; Feres, Omar ; Vilar, Fernando C. ; Gaspar, Gilberto G. ; Santos, Isabel K. F. M. ; Fernandes, Ana P. M. ; Maruyama, Sandra R. ; Russo, Elisa M. S. ; Bonato, Vania L. D. ; Cardoso, Cristina R. B. ; Dias-Baruffi, Marcelo ; Faccioli, Lucia H. ; Sorgi, Carlos A. ; ImmunoCovid Sdy Grp

• Document type: Journal article
• Source: Viruses-Basel; v. 15, n. 2, p. 22-pg., 2023-02-01.

Abstract

COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course. (AU)

• FAPESP's process: 15/00658-1 - New functional aspects of eicosanoids
• Grantee: Lúcia Helena Faccioli
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 21/04590-3 - Exploratory analysis of functional lipidomics in the COVID-19 pathophysiology: molecular targets, metabolism and biochemical reprogramming due to hypoxia
• Grantee: Carlos Arterio Sorgi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/08534-8 - Lipidomic analysis using high-resolution mass spectrometry for molecular profile determination in plasma of patients infected with SARS-CoV-2
• Grantee: Malena Martínez Pérez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/05207-6 - Prospective evaluation of lipid mediators production on the immune response against COVID-19: search for biomarkers and new therapeutic targets in the evolution of the disease
• Grantee: Lúcia Helena Faccioli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/07125-6 - New functional aspects of eicosanoids
• Grantee: Lúcia Helena Faccioli
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/07287-2 - Characterization and immunomodulatory potential of extracellular vesicles from macrophages stimulated with SARS-CoV-2 particles
• Grantee: Jonatan Constança Silva de Carvalho
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/05270-0 - Role of human airway epithelial cell death in the inflammation caused by 2019-nCoV and confirmation by transcriptional analysis of infected patients
• Grantee: Vânia Luiza Deperon Bonato
• Support Opportunities: Regular Research Grants