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Evaluation of the effects of direct and remote ischemic preconditioning in liver transplantation in pigs

Grant number: 14/25676-0
Support type:Regular Research Grants
Duration: February 01, 2016 - July 31, 2018
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Uenis Tannuri
Grantee:Uenis Tannuri
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Alessandro Rodrigo Belon ; Ana Cristina Aoun Tannuri ; Jose Luiz de Figueiredo ; Maria Cecília de Mendonça Coelho

Abstract

Liver transplantation (LT) is the only acceptable and effective method of treatment for patients with end-stage liver failure. LT can prolong and improve the quality of life of these patients. The progress in the training of professionals involved in trans and post-operative management, combined with new regimes of immunosuppressive treatments, helped to improve the short- and long-term results of these transplants. However, despite these advances, the ischemia and reperfusion (I/R) injury, during the removal and implantation of the graft remains an important cause of primary dysfunction and also relates to cases of acute and chronic rejection.In order to minimize the deleterious effects of I/R in the grafts, the development and use of new solutions for grafts conservation, for example, contributed positively to the success of the liver transplants. New strategies are being studied / developed. Ischemic preconditioning (IPC), which is a maneuver that generate brief periods of ischemia followed by brief periods of reperfusion prior to a ischemic insult (transplant), may help the organ (liver) to tolerate long period of ischemia and subsequent reperfusion. IPC is considered an endogenous protective mechanism in both the donor and recipient. The release of substances in the bloodstream, after IPC, can develop protective effects, eg reduction of apoptosis and cell necrosis of the graft, and consequently increases in liver transplants survival rate.IPC can be direct (in the target organ) or indirect (remote). In the direct IPC (DIPC), the biggest disadvantage is the mechanical stress on the main vascular structures of the organ. Remote IPC (RIPC) is the procedure where the target organ does not suffer episodes of brief ischemia, in other words, another organ is ischemic for a short period and the protective effect acts in the target organ. In literature there are few studies reporting the possible beneficial effect of IPC in liver transplantation in large animals. The purpose of the project and observe the effects of IPC in orthotopic liver transplantation model in pigs with similar weight, since the efficiency of these techniques has been proven both in liver transplant and in the syndromes of I/R in small animals.In this study, we use 48 pigs (24 donors and 24 recipients). The animals will be allocated into the following groups: control group (GCT N = 6); PCID group donor (GPCIDD; N = 6); Group PCIR receiver (GPCIRR N = 6) Group PCID and the donor and the receiver PCIR (GPCIDD GPCIRR + N = 6). After the transplantation, the animals will be placed in individual pens where they will receive painkillers 8/8h and antibiotics 12/12h. The cervical, venous and arterial access will be held for collection of blood samples every 3 hours for a period of 24 hours, after the experimental period the animals will be euthanized for collection of renal biopsies, lung, liver and bowel. Hemodynamic (heart rate, mean arterial pressure and central venous pressure), oxygen transport (oxygen content, hemoglobin, oxygen saturation, oxygen partial pressure and partial pressure of carbon dioxide), laboratory variables (pH, base excess, bicarbonate ions, lactate, hematocrit, sodium, calcium and glucose), serum AST, ALT, urea, creatinine and inflammatory cytokines (IL 1², IL6, IL10, IFN ( e TNF ±), molecular analysis (pro-apoptotic gene: Bax; antiapoptotic gene: Bcl-XL; gene cell proliferation: IL-6 and nitric oxide generator gene: eNOS), immunohistochemical and histopathological (liver, kidney, intestine and lung) analyzes will be compared in order to find differences between groups. Evaluating the effects of local and systemic treatments and whether there are cumulative effects of subsequent treatments when made. (AU)