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| Author(s): |
Camila Bononi de Almeida
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2011-07-29 |
| Examining board members: |
Nicola Amanda Conran Zorzetto;
Alessandra Gambero;
Licio Augusto Velloso;
Joyce Maria Annichino Bizzacchi;
José Artur Bogo Chies
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| Advisor: | Nicola Amanda Conran Zorzetto; Fernando Ferreira Costa |
| Abstract | |
Sickle Cell Disease (SCD) is a disorder of hemoglobin synthesis, caused by a point mutation, and resulting in the production of abnormal sickle hemoglobin, HbS. The consequence of low oxygen levels is HbS polymerization, which is responsible for the vaso-occlusive phenomenon that is the hallmark of the disease. SCD is a chronic inflammatory disease characterized by alterations in cytokine levels and an increase in leukocytes number and endothelial cell injury. Leukocytes play an important role in SCD since their recruitment to the microvasculature, consequent adhesion to the vessel wall, and interactions with other cells may interrupt the blood flow and culminate in vaso-occlusion. Therapeutic strategies for SCD treatment are based on three points: 1) reduction of intracellular HbS concentration, for example, by increasing the erythrocytic HbF concentration; 2) reduction of inflammatory processes and oxidative stress; 3) inhibition of cellular adhesion and, as a consequence, a reduction in vaso-occlusion. HU is a chemotherapeutic drug used for SCD treatment. This drug is able to increase HbF concentrations and reduce white blood cells counts, although it has some adverse effects and some patients do not respond to this therapy. Thus, it is necessary to fully understand the mechanisms that contribute to the vaso-occlusive process, including the role of the leukocytes in this phenomenon. The goals of this study are: 1) To check the influence of factors present in SCD serum on mechanisms that may affect the neutrophil count and oxidative stress generation; 2) understand the role of neutrophils in the initiation and propagation of vascular inflammation and vaso-occlusion. Date indicate that factors present in the SCD serum are able to alter neutrophil apoptosis and induce reactive oxygen species (ROS) generation, possibly by the activation of the NADPH enzyme expressed in these cells. Additionally, results obtained from a SCD inflammatory mouse model indicate that an activation of the cGMP - dependent pathway can inhibit neutrophil adhesion to the vascular endothelium cells after inflammatory induction and that drugs that amplify the effects of HU may represent a potential new therapy for SCD treatment (AU) | |
| FAPESP's process: | 07/58533-3 - Role of leukocytes in the pathophysiology of sickle cell anemia |
| Grantee: | Camila Bononi de Almeida |
| Support Opportunities: | Scholarships in Brazil - Doctorate |