Platelet adhesion mediated by fibrinogen-intercelllular adhesion molecule-1 binding induces tissue injury in the postischemic liver in vivo.
BACKGROUND
Platelets are thought to be involved in the induction of hepatic ischemia-reperfusion (I/R) injury. The mechanisms of platelet adhesion in the hepatic microvasculature and the role of platelets in the pathogenesis of I/R-induced liver damage in vivo remain unclear.


METHODS
In C57BL/6 mice, platelet- and leukocyte-endothelial cell interactions were quantitatively analyzed using intravital fluorescence microscopy in sham-operated animals, after warm lobar hepatic I/R (90/20 min) in wild-type and intercellular adhesion molecule (ICAM)-1-deficient mice, and after I/R in wild-type mice treated with an antifibrinogen antibody. Fibrinogen deposition on the endothelium was detected by intravital microscopy and by immunostaining. Reperfusion injury was assessed by measurement of liver enzyme and caspase-3 activities and of lipid peroxidation.


RESULTS
Hepatic I/R induced fibrinogen deposition on hepatic endothelium, followed by a dramatic increase in the number of firmly adherent platelets in the liver microvasculature. Simultaneously, the number of adherent leukocytes in postsinusoidal venules and the aspartate aminotransferase/alanine aminotransferase and caspase-3 activities were elevated. Although ICAM-1 deficiency attenuated postischemic adherence of both platelets and leukocytes, the application of an antifibrinogen antibody selectively reduced the number of adherent platelets but did not influence leukocyte adhesion. The selective blockade of platelet adherence significantly prevented the postischemic increase in liver enzyme and caspase-3 activities. Furthermore, sinusoidal perfusion failure and lipid peroxidation were attenuated in the treated group.


CONCLUSIONS
These in vivo data show that platelet adhesion mediated through fibrinogen deposition on ICAM-1 expressed on the endothelium of postischemic hepatic microvessels induces microvascular injury and hepatocellular apoptosis after I/R of the liver during early reperfusion.
D000818:Animals; D001160:Arterioles / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005340:Fibrinogen / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D015227:Lipid Peroxidation; D008099:Liver / Q000502:physiology*; D008102:Liver Circulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D010973:Platelet Adhesiveness / Q000502:physiology*; D015427:Reperfusion Injury / Q000097:blood / Q000503:physiopathology*
D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen