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Role of omega-3 or 6 in the cell death induced by kinins in ischemia and reperfusion injury in rat liver

Grant number: 16/03049-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2016
Effective date (End): February 04, 2018
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Márcia Regina Nagaoka
Grantee:Gianlucca Nadas Damiani
Home Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil

Abstract

There are several situations that can cause ischemia in an organ, with missing or decreased blood flow and oxygen supply and nutrients. The ischemia-reperfusion injury (IRI) is the cellular damage in ischemic organ, after the restoration of blood flow. The knowledge of the mechanisms of this damage is of great interest, as part of the pathophysiology of numerous medical conditions, including liver transplantation, and this injury may affect the adaptation of the graft (10 to 30% of cases) or at worst possibilities, cause immediate dysfunction (up 5%). Rat liver IRI is characterized by two cell death process, with an initial event of sinusoidal endothelial cell necrosis, followed by a late phase of hepatocytes apoptosis.Recent studies showed the relation between IRI and the essential fatty acids supplementation, represented by constituents of the omega-3 family (É-3) and omega-6 (É-6), which are important for the growth and development of the organism, prevention of coronary heart disease, hypertension, arthritis, cancer, and other inflammatory and autoimmune conditions. A possible relationship between these two factors is the production of eicosanoids, which are very active molecules during the inflammatory response, a key event in the IRI.Another important modulator of the liver, related to the IRI, is the kinin system, represented mainly by bradykinin (BK). The biological actions and pharmacological effects of BK are mediated by two receptors, constitutive (B2R) and inducible (B1R). The main agonist B1R is des-Arg9-BK (DABK), and this receptor is absent in normal tissues, and its expression can be induced by inflammatory stimuli.Recent studies in our laboratory have confirmed the expression of B1R after hepatic IRI and, in addition, an antagonist of this receptor, the des-Arg9 [Leu8]-BK decreased apoptotic cell death, apparently without reducing the activity of caspase-3. The B2R antagonist, HOE-140, was able to reduce cell death by necrosis.The role of the kinin system in hepatic IRI is little studied and the goal of this project is to study cell death induced by kinins in ischemia and reperfusion in rat liver previously (8 weeks) fed with an enriched diet with omega-3 or omega-6. Cell death will be assessed by histological analysis (trypan blue), ELISA, enzymatic activity of caspases and Western Blot for other apoptosis-related proteins (Bad, Bax and Bcl-2). It is expected with this project to better understand the process of cell death in the IRI and thus improve the quality of the liver to be transplanted and the subsequent survival of the recipient.