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Title Quebra da barreira endotelial no choque séptico = caracterização, mecanismos e novos mediadores = Endothelial barrier breakdown in septic shock:: Endothelial barrier breakdown in septic shock : characterization, mechanisms and new mediators
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University/Publisher Universidade Estadual de Campinas
Abstract Abstract: Endothelial barrier (EB) breakdown is regarded as a hallmark of sepsis and pathways that participate in the physiological regulation of EB integrity are emerging as promising targets in septic shock. The aim of our study was to investigate the effect of serum from patients with septic shock on EB integrity, and to explore the role of extracellular heme, VEGF-A and angiopoietin-2 (Ang-2) as potential mediators of microvascular permeability in human septic shock. Methodology: Serum from patients with septic shock and healthy volunteers was used to stimulate HUVEC monolayers. EB integrity was assessed by electric cell-substrate impedance sensing, which measures the transendothelial electrical resistance (TEER) of endothelial cell monolayers, and by immunofluorescence-based morphological studies of cell-cell junctions. Serum levels of classical mediators of EB function, VEGF-A, Ang-2 and heme were measured in the same samples. The effect of heme on EB function was then assessed using the same experimental model. From a mechanism standpoint, we evaluated the effect of heme on the internalization and phosphorylation of the cell-cell junction protein, VE-cadherin. Results: Sera from patients with septic shock (n = 18) induced a more pronounced decrease of TEER than sera from healthy volunteers (n = 11), and these alterations were associated with a increase in the extension of intercellular gaps. Serum levels of heme in septic shock were similar to those described in sickle cell anemia. Moreover, only heme levels correlated with both sepsis severity and with EB disruption. Finally, free heme was capable to induce a marked and transient increase in EB permeability as measured by both functional and morphological assays. Preliminary results showed a trend increasing the level of phosphorylation and internalization of VE-cadherin in heme-stimulated endothelial cells. Conclusion: Our study showed that serum from patients from septic shock is sufficient to induce EB breakdown, and that heme, present in plasma of these patients in levels similar to those observed in other hemolytic anemias can also induce the transient disruption of endothelial barrier. We also showed that free heme may play a role in the internalization and phosphorylation of VE-cadherin, although more data will be required to confirm or refute this fact. These results pave the way for the investigation of therapeutic strategies aimed at limiting the availability of extracellular heme in human sepsis
Subjects/Keywords Choque séptico; Células endoteliais; Junções aderentes; Caderinas; Shock, Septic; Endothelial cells; Adherens junctions; Cadherins
Contributors UNIVERSIDADE ESTADUAL DE CAMPINAS (CRUESP); Paula, Erich Vinicius de, 1972- (advisor); Universidade Estadual de Campinas. Faculdade de Ciências Médicas (institution); Programa de Pós-Graduação em Ciências Médicas (nameofprogram); Oliveira, Rodrigo Bueno de (committee member); Gontijo, Jose Antonio Rocha (committee member); Salomão, Reinaldo (committee member); Fidalgo, Thereza Christina Barja (committee member)
Country of Publication br
Record ID oai:repositorio.unicamp.br:REPOSIP/330381
Repository unicamp
Date Indexed 2020-09-09
Issued Date 2017-01-01 00:00:00
Note [] Orientador: Erich Vinicius de Paula; [] Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas; [degreelevel] Doutorado; [degreediscipline] Patologia Clinica; [degreename] Doutora em Ciências; [sponsordocumentnumber] 2014/00984-3; [sponsor] FAPESP; [sponsor] CAPES;

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