Control of Sepsis-induced vital organs damage through glycolysis pathway modulation

• Grant number: 17/03775-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2017
• End date: March 31, 2019
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Braulio Henrique Freire Lima
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Sepsis is a complex syndrome induced by microorganisms in which the host suffer from physiological, immune and biochemical dysfunctions leading to severe organ lesions following by high mortality rates (30 to 60%; CHAARI et al., 2016; DELLINGER et al., 2013; SINGER et al., 2016). The Sepsis pathophysiology is characterized by the presence of microorganisms or their byproducts in the blood stream and by a massive release of inflammatory mediators by the host immune cells. The combination of these two factors activates the circulating neutrophils which traps insight vital host organs, where they release, among other cytotoxic mediators, the Neutrophil Extracellular Traps (NETs). The literature shows that NETs contribute to the organ failure observed in sepsis. NETs are also involved in tissue lesion observed in several other diseases such as Diabetes and Arthritis (BRINKMANN et al., 2004; NAUSEEF; BORREGAARD, 2014). In the Sepsis context, NETs are involved in tissue damage in several organs, including lungs, kidneys and liver (CZAIKOSKI et al., 2016). Despite the mechanism involved in NETs production is not well described during Sepsis episodes, there is evidence that an early event of the process is the activation of PADI4, a calcium dependent enzyme. Recently, a link between cellular metabolism changes and cellular activation of innate immune response has being consolidated (CHANG et al., 2015; HO et al., 2015; RODRÍGUEZ-ESPINOSA et al., 2015). However, the involvement of the cellular metabolism and the generation of NET was not well investigated. A preliminary study from our group shows that dampening the activity of the glycolytic pathway results in less NETs formation. Therefore, the present study aims to evaluate the importance of the immunometabolism for NETs production and sepsis worsening. We will also investigate a new therapeutic approach for the prevention of severe sepsis by combining the traditional antibiotic treatment with the modulation of the cellular metabolism. (AU)