Document Detail


Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock.
MedLine Citation:
PMID:  23324886     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 β-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.
Authors:
Devendra A Sawant; Binu Tharakan; Richard P Tobin; Hayden W Stagg; Felicia A Hunter; M Karen Newell; W Roy Smythe; Ed W Childs
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  39     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-06-07     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  United States    
Other Details:
Languages:  eng     Pagination:  161-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD95 / antagonists & inhibitors*
Apoptosis / physiology*
Capillary Permeability / physiology*
Caspase 3 / metabolism
Caspase Inhibitors / pharmacology
Cell Communication / physiology
Endothelium, Vascular / metabolism
Fas Ligand Protein / antagonists & inhibitors*
Lung / cytology,  metabolism*
Male
Microvessels / enzymology,  physiology
Rats
Rats, Sprague-Dawley
Shock, Hemorrhagic / metabolism*
Grant Support
ID/Acronym/Agency:
1K01HL07815-01A1/HL/NHLBI NIH HHS; K01 HL076815/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Caspase Inhibitors; 0/Fas Ligand Protein; EC 3.4.22.-/Caspase 3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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