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Study of processes inflammatory and angiogenic in a model of chronic hemolysis in vivo and effects of hydroxyurea

Grant number: 16/10542-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2016
Effective date (End): September 30, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Nicola Amanda Conran Zorzetto
Grantee:Érica Martins Ferreira Gotardo
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Hemolysis is a pathological condition characterized by the destruction of the red blood cells and their consequent release of hemoglobin (Hb) and heme into the plasma. Various diseases and pathological conditions of differing etiologies are associated with hemolysis, which can be triggered by both intrinsic and extrinsic factors such as, respectively, sickle cell anemia or certain bacterial or parasitic infections. Emerging evidence suggests that patients with hemolytic diseases may present chronic inflammation and vascular damage when Hb and free heme release into the plasma exceeds their removal by the innate homeostatic defense system. Excess plasma Hb and heme can decrease nitric oxide bioavailability, and incur endothelial dysfunction and inflammatory events. Hydroxyurea (HU) is therapeutic agent that is frequently employed as a therapy for treating hemoglobinopathies, in particular sickle cell anemia. Though not well understood, this agent has anti-inflammatory actions and we suggest that this drug may hold potential for use in other diseases where excessive intravascular hemolysis occurs. To our knowledge, there is currently no experimental animal model that mimics conditions of prolonged or chronic hemolysis. The first objective of this study is to standardize and characterize an experimental model of chronic hemolysis via the repeated administration of intravenous water in C57BL/6 mice. Once this model is standardized, we will evaluate inflammatory and angiogenic processes (mechanisms of neovascularization that are stimulated by inflammatory processes) in the blood vessels and tissues of the mice during the progression of hemolysis. Finally, we will determine the ability of HU to modulate these possible inflammatory and angiogenic events during the in vivo chronic hemolytic process. Understanding the pathophysiological mechanisms of intravascular hemolysis, and its consequences, and studying approaches that can be used to neutralize its effects may be important for the development of new treatment strategies of diseases in which hemolysis occurs.