Evaluation of cellular metabolism in endotoxin tolerant peripheral blood mononuclear cells

• Grant number: 18/19855-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2018
• End date: October 31, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Reinaldo Salomão
• Grantee: Mônica Bragança Sousa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 17/21052-0 - Sepsis: mechanisms, therapeutic targets and epidemiology, AP.TEM

Abstract

Sepsis is the leading cause of death in ICU and is defined as a dysregulated host response to infection, which causes organ dysfunction. Recent data indicate that septic patients present both immune suppression and inflammation simultaneously, so there is a modulation of the immune response. Several studies show the importance of energy metabolism in immune regulation, for example, different cells of innate and adaptive responses when activated switch their metabolism from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as Warburg effect, and this shift implies in the cell function. There is evidence in literature that cellular reprogramming in sepsis is related to cellular metabolism. The immunomodulation that occurs in leukocytes from septic patients is similar to the reprogramming observed in endotoxin tolerance model, in which pre-exposure to LPS inhibits the biological response to a re-exposure with high doses of LPS. Different studies show that the effect of pre-exposure is related to metabolic changes, however, there are few studies demonstrating how the metabolic change is related to the immunomodulation observed after the re-exposure to LPS. Thus, the aim of this project is to analyze how the cellular metabolism is related to the response observed in endotoxin tolerant peripheral blood mononuclear cells. Tolerance to LPS will be assessed measuring pro inflammatory cytokines production by flow cytometry. The cellular metabolism will be evaluated with measurements of ATP, NAD and Lactate production; the consumption of oxygen and extracellular acidification will be analyzed as well. Understanding how metabolic change occurs after tolerance induction and how this change relates to cellular reprogramming might improve the comprehension of function alterations observed in leukocytes from septic patients.