Evaluation of the functional alterations of adherens junctions induced by septic shock in endothelial cell cultures

• Grant number: 12/10859-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2012
• End date: July 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Gleice Regina de Souza
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The breakdown of endothelial barrier integrity is a fundamental mechanism of the pathophysiology of sepsis, which only recently became a focus of studies about target-specific therapies. As a result, there is to date no advanced programs for developing new drugs for sepsis in the area of endothelial barrier integrity maintenance. "Adherens" junctions are the main structure responsible for maintaining the integrity of the endothelial barrier (EB). The main component of these junctions is VE-cadherin, a transmembrane protein that is associated with several other cytoplasmic proteins, anchoring these junctions to the cytoskeleton. The binding of the extracellular portions of VE-cadherin form adjacent endothelial cells (EC) is the primary mechanism for maintaining the BE. Factors that lead to EB breakdown, such as inflammatory cytokines and VEGF, have in common the ability to induce the internalization of VE-cadherin, thereby disrupting these junctions. It has been recently demonstrated that the binding of protein p120ctn with an intracellular domain of VE-cadherin is a critical event for the retention of the protein on the cell surface, giving a characteristic of this interaction potential therapeutic target. However, the relevance of this mechanism in human sepsis remains unexplored. Studies have shown that the plasma of septic patients is able to increase the permeability of EC in culture. In this work we intend to evaluate the time-course of the relative expression of VE-cadherin and p120ctn in cultured EC incubated with plasma from patients with septic shock obtained in distinct moments of clinical evolution, in order to gain insights on the role of this mechanism in human sepsis and maybe explore its potential therapeutic significance.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SOUZA, Gleice Regina de. In vitro assessment of the effect of free Heme on activation of coagulation and breach of endothelial barrier. 2014. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.