P-selectin mediates platelet-endothelial cell interactions and reperfusion injury in the mouse liver in vivo.
Platelets are suggested to participate in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. This study was designed to analyze platelet-endothelial cell interactions in the postischemic mouse liver in vivo and to define the role of endothelial versus platelet P-selectin for these interactions. Platelet-endothelial cell interactions were quantitatively analyzed using intravital fluorescence microscopy after lobar hepatic I/R in C57BL/6 wild-type and P-selectin-deficient mice after infusion of ex vivo rhodamine-6G-labeled wild-type and P-selectin-deficient platelets. Reperfusion injury and apoptosis were assessed by established methods. In wild-type animals, hepatic I/R caused significantly enhanced platelet-endothelial cell interactions in terminal arterioles and postsinusoidal venules as well as platelet stagnation in sinusoids. Concomitantly, transaminase and caspase-3 activities were elevated and sinusoidal perfusion was impaired. In contrast, platelet-endothelial cell interactions were nearly absent in arterioles and venules of mice lacking endothelial P-selectin, irrespective of the presence of P-selectin on infused platelets, but still significantly elevated in sinusoids. Simultaneously, sinusoidal perfusion failure was ameliorated, and transaminase- and caspase-3 activities were significantly reduced in P-selectin-deficient mice as compared with wild-type animals. The present intravital microscopic study provides, for the first time, quantitative analyses of platelet-endothelial cell interactions in the postischemic hepatic microcirculation. Our in vivo data show that endothelial P-selectin is critical for postischemic platelet-endothelial cell interactions within hepatic presinusoidal arterioles and postsinusoidal venules. P-selectin deficiency prevents microvascular injury and apoptosis after warm hepatic I/R.
Khandoga
Andrej
A
Institute for Surgical Research, University of Munich, Germany.
Biberthaler
Peter
P
Enders
Georg
G
Teupser
Daniel
D
Axmann
Stefan
S
Luchting
Benjamin
B
Hutter
Joerg
J
Messmer
Konrad
K
Krombach
Fritz
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D016031:Liver Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology
D019007:P-Selectin