Regulation of E-selectin expression in postischemic intestinal microvasculature.
Monolayers of cultured endothelial cells exposed to hypoxia-reoxygenation exhibit a transcription-dependent increase in E-selectin expression and E-selectin-dependent neutrophil-endothelial cell adhesion. The overall objectives of this study were 1) to determine whether ischemia-reperfusion (I/R) promotes upregulation of E-selectin in vivo; 2) if so, to define the mediators of this response; and 3) to assess the contribution of E-selectin to I/R-induced neutrophil recruitment. The dual-radiolabeled monoclonal antibody (MAb) technique was used to measure E-selectin expression in the intestinal vasculature. Ischemia was induced by complete occlusion (30-60 min) of the superior mesenteric artery followed by 3-24 h of reperfusion. Increasing durations of ischemia elicited progressively increasing (2- to 5-fold) levels of E-selectin expression, with the peak response noted after 45 min of ischemia and 5 h of reperfusion. Subsequent experiments revealed that I/R-induced increase in E-selectin expression (at 5 h) is significantly blunted in transgenic mice that overexpress Cu,Zn-superoxide dismutase or by treatment of wild-type mice with either a blocking antibody against tumor necrosis factor (TNF)-alpha or an inhibitor of nuclear factor-kappaB (NF-kappaB) activation (PS341). Administration of an E-selectin-specific MAb dramatically reduced I/R-induced recruitment of neutrophils in the intestine. These findings suggest that superoxide and TNF-alpha mediate gut I/R-induced E-selectin expression via an NF-kappaB-dependent mechanism; this upregulation of E-selectin contributes significantly to I/R-induced neutrophil recruitment.
Russell
J
J
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Epstein
C J
CJ
Grisham
M B
MB
Alexander
J S
JS
Yeh
K Y
KY
Granger
D N
DN
D000818:Animals; D016207:Cytokines / Q000502:physiology; D019040:E-Selectin / Q000097:blood*; D006098:Granulocytes / Q000502:physiology; D007422:Intestines / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D016328:NF-kappa B / Q000502:physiology; D015424:Reperfusion; D019087:Selectins / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D016207:Cytokines; D019040:E-Selectin; D016328:NF-kappa B; D019087:Selectins; D013481:Superoxides