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Assessment of the effects of 172 - estradiol on liver injury by occlusion total of the proximal portion of descending aortic in male rats

Grant number: 16/14025-3
Support type:Regular Research Grants
Duration: March 01, 2017 - August 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Ricardo Ribeiro Dias
Grantee:Ricardo Ribeiro Dias
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Ana Cristina Breithaupt Faloppa ; Luiz Felipe Pinho Moreira ; Marcelo Luiz Peixoto Sobral ; Paulina Sannomiya

Abstract

Aortic diseases present high morbidity and mortality and are responsible for a significant portion of deaths from cardiovascular disease. The surgical approach in complex cases of thoracic aorta often requires systemic circulatory arrest in varying degrees of hypothermia, time sometimes extended. As a result of this period of ischemia to the body following perfused by thoracic aorta distal to the subclavian artery may occur several complications related to the known phenomenon of ischemia-reperfusion (I / R). The injury I / R liver, often present in this type of operation, resulting in varying degrees of secondary perioperative bleeding coagulopathy having a direct impact on morbidity and mortality.In liver damage after I / R, it is observed that its microcirculation is the main aim of this involvement. It has been shown that different mechanisms contribute to the manifestation of injury, such as oxidative stress, inflammation and mitochondrial damage, activation of Kupffer cells, endothelial damage, abnormal release of nitric oxide (NO), vasoconstriction and inadequate vasodilation due to decreased NO. The lesion I / R liver starts the cascade of inflammatory mediators and activated Kupffer cell promote the release of pro-inflammatory cytokines, including tumor necrosis factor (TNF-a) and interleukin-6. These cytokines increase the inflammatory response in I / R liver resulting in hepatocellular dysfunction due to hepatic necrosis and apoptosis.In order to reduce the harmful effects caused by I / R liver, we have attempted to identify mechanisms to reduce this tissue damage. Options such as regional or remote ischemic preconditioning, hypothermia, topiramate and the use of hormones, such as estradiol, have been successfully tested in rats in order to reduce the damage caused by localized ischemia and / or partial liver.The study aims to analyze the changes of platelet flow in the hepatic microcirculation induced phenomenon I / R secondary to occlusion of the proximal descending aorta and analyze possible changes in the secondary coagulation of these changes. As well as evaluate the benefits of intravenous use of 17²-estradiol. Fourty male Wistar rats divided into 4 groups of 10 animals to be submitted to surgical manipulation with induction of ischemia and reperfusion injury with and without intravenous infusion of 17²-estradiol will be used. Initially, the blood platelets will be collected and prepared for the study. hemodynamics and blood gas will be analyzed, in addition to other variables: 1 - markers of liver damage (liver enzymes); 2 - Evaluation of liver perfusion (intravital fluorescence microscopy and sinusoidal perfusion); 3 - Evaluation of the response to vascular I / R in liver (iNOS Immunohistochemistry for research and eNOS endothelin, assessment of pro-inflammatory cytokines IL1Beta; TNF-alpha and interferon (IFN)-y, immunohistochemistry adhesion molecules Research, degree of cell damage (hepatocellular apoptosis) - activity of caspase-3 (pro-apoptotic) and BCL2 (anti-apoptotic) and 4 - Evaluation of liver damage and consequent alteration of the clotting (coagulation, platelet count and thromboelastometry). (AU)