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Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.
Sawant, Devendra A; Tharakan, Binu; Tobin, Richard P; Stagg, Hayden W; Hunter, Felicia A; Newell, M Karen; Smythe, W Roy; Childs, Ed W.
Afiliação
  • Sawant DA; Department of Surgery, Morehouse School of Medicine, Atlanta, Georgia 30310, USA.
Shock ; 39(2): 161-7, 2013 Feb.
Article em En | MEDLINE | ID: mdl-23324886
ABSTRACT
Hemorrhagic shock (HS)-induced microvascular hyperpermeability poses a serious challenge in the management of trauma patients. Microvascular hyperpermeability occurs mainly because of the disruption of endothelial cell adherens junctions, where the "intrinsic" apoptotic signaling plays a regulatory role. The purpose of this study was to understand the role of the "extrinsic" apoptotic signaling molecules, particularly Fas-Fas ligand interaction in microvascular endothelial barrier integrity. Rat lung microvascular endothelial cells (RLMECs) were exposed to HS serum in the presence or absence of the Fas ligand inhibitor, FasFc. The effect of HS serum on Fas receptor and Fas ligand expression on RLMECs was determined by flow cytometry. Endothelial cell permeability was determined by monolayer permeability assay and the barrier integrity by ß-catenin immunofluorescence. Mitochondrial reactive oxygen species formation was determined using dihydrorhodamine 123 probe by fluorescent microscopy. Mitochondrial transmembrane potential was studied by fluorescent microscopy as well as flow cytometry. Caspase 3 enzyme activity was assayed fluorometrically. Rat lung microvascular endothelial cells exposed to HS serum showed increase in Fas receptor and Fas ligand expression levels. FasFc treatment showed protection against HS serum-induced disruption of the adherens junctions and monolayer hyperpermeability (P < 0.05) in the endothelial cells. Pretreatment with FasFc also decreased HS serum-induced increase in mitochondrial reactive oxygen species formation, restored HS serum-induced drop in mitochondrial transmembrane potential, and reduced HS serum-induced caspase 3 activity in RLMECs. These findings open new avenues for drug development to manage HS-induced microvascular hyperpermeability by targeting the Fas-Fas ligand-mediated pathway.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Choque Hemorrágico / Permeabilidade Capilar / Apoptose / Receptor fas / Proteína Ligante Fas / Pulmão Limite: Animals Idioma: En Revista: Shock Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Choque Hemorrágico / Permeabilidade Capilar / Apoptose / Receptor fas / Proteína Ligante Fas / Pulmão Limite: Animals Idioma: En Revista: Shock Ano de publicação: 2013 Tipo de documento: Article