Early organ-specific endothelial activation during hemorrhagic shock and resuscitation.
Multiple organ dysfunction syndrome (MODS) is a complication of hemorrhagic shock (HS) and related to high morbidity and mortality. Interaction of activated neutrophils and endothelial cells is considered to play a prominent role in the pathophysiology of MODS. Insight in the nature and molecular basis of endothelial cell activation during HS can assist in identifying new rational targets for early therapeutic intervention. In this study, we examined the kinetics and organ specificity of endothelial cell activation in a mouse model of HS. Anesthetized male mice were subjected to controlled hemorrhage to a MAP of 30 mmHg. Mice were killed after 15, 30, 60, or 90 min of HS. After 90 min of hemorrhagic shock, a group of mice was resuscitated with 6% hydroxyethyl starch 130/0.4. Untreated mice and sham shock mice that underwent instrumentation and 90 min of anesthesia without shock served as controls. Gene expression levels of inflammatory endothelial cell activation (P-selectin, E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) and hypoxia-responsive genes (vascular endothelial growth factor and hypoxia-inducible factor 1alpha) were quantified in kidney, liver, lung, brain, and heart tissue by quantitative reverse-transcription-polymerase chain reaction. Furthermore, we examined a selection of these genes with regard to protein expression and localization using immunohistochemical analysis. Induction of inflammatory genes occurred early during HS and already before resuscitation. Expression of adhesion molecules was significantly induced in all organs, albeit to a different extent depending on the organ. Endothelial genes CD31 and VE-cadherin, which function in endothelial cell homeostasis and integrity, were not affected during the shock phase except for VE-cadherin in the liver, which showed increased mRNA levels. The rapid inflammatory activation was not paralleled by induction of hypoxia-responsive genes. This study demonstrated the occurrence of early and organ-specific endothelial cell activation during hemorrhagic shock, as presented by induced expression of inflammatory genes. This implies that early therapeutic intervention at the microvascular level may be a rational strategy to attenuate MODS.
van Meurs
Matijs
M
Department of Anaesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands. m.van.meurs@anest.umcg.nl
Wulfert
Francis M
FM
Knol
Ageeth J
AJ
De Haes
Ann
A
Houwertjes
Martin
M
Aarts
Leon P H J
LP
Molema
Grietje
G
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D012151:Resuscitation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D019040:E-Selectin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018799:Intercellular Adhesion Molecule-1; D019007:P-Selectin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5