Khandoga Andrej, Biberthaler Peter, Enders Georg, Axmann Stefan, Hutter Joerg, Messmer Konrad, Krombach Fritz
Transplantation. 2002 Sep 15;74(5):681-8. doi: 10.1097/00007890-200209150-00016.
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.
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.
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.
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.
血小板被认为参与了肝缺血再灌注（I/R）损伤的诱导过程。血小板在肝微血管中的黏附机制以及血小板在体内I/R诱导的肝损伤发病机制中的作用仍不清楚。
在C57BL/6小鼠中，使用活体荧光显微镜对假手术动物、野生型和细胞间黏附分子（ICAM）-1缺陷型小鼠进行温性肝叶I/R（90/20分钟）后以及用抗纤维蛋白原抗体处理的野生型小鼠进行I/R后，对血小板与白细胞-内皮细胞相互作用进行定量分析。通过活体显微镜检查和免疫染色检测纤维蛋白原在内皮上的沉积。通过测量肝酶和半胱天冬酶-3活性以及脂质过氧化来评估再灌注损伤。
肝I/R诱导纤维蛋白原在肝内皮上沉积，随后肝微血管中牢固黏附的血小板数量急剧增加。同时，肝血窦后小静脉中黏附的白细胞数量以及天冬氨酸转氨酶/丙氨酸转氨酶和半胱天冬酶-3活性升高。尽管ICAM-1缺陷减弱了缺血后血小板和白细胞的黏附，但应用抗纤维蛋白原抗体选择性地减少了黏附血小板的数量，但不影响白细胞黏附。选择性阻断血小板黏附可显著预防缺血后肝酶和半胱天冬酶-3活性的增加。此外，治疗组的肝血窦灌注衰竭和脂质过氧化得到减轻。
这些体内数据表明，通过纤维蛋白原沉积在内皮上表达的ICAM-1介导的血小板黏附，在肝I/R早期再灌注期间诱导微血管损伤和肝细胞凋亡。
