4��0.9 up to 39.1��3.7% in BDL mice (Figure 5, P<0.05 vs sham, Enzalutamide solubility n=7�C8). The number of non-perfused sinusoids after BDL decreased to 15.7��3.2% in platelet-depleted animals (Figure 5, P<0.05 vs Control ab+BDL, n=7�C8). Moreover, administration of the ab directed against P-selectin reduced perfusion failure to 16.5��2.8% in BDL mice (Figure 5, P<0.05 vs Control ab+BDL, n=7�C8). We also noted numerous and widespread aggregates (that is more than three platelets) of platelets in the hepatic microvasculature after ligation of the common bile duct. The number of these platelet aggregates increased by 16- and 30-fold in sinusoids and postsinusoidal venules, respectively, in BDL mice (Figure 6, P<0.05 vs sham, n=7�C8).

Administration of the anti-GP-1b�� and the anti-P-selectin ab abolished BDL-induced formation of platelet aggregates in the hepatic microcirculation (Figure 6, P<0.05 vs Control ab+BDL, n=7�C8). Figure 5 Sinusoidal perfusion failure 12h after ligation of the common bile duct. Mice were pretreated i.v. with an iso-type control antibody (Control ab), an antibody against GP1b�� (anti-GP1b�� ab) or against P-selectin (anti-P-selectin ... Figure 6 Platelet aggregates in (a) sinusoids and (b) postsinusoidal venules 12h after ligation of the common bile duct. Mice were pretreated i.v. with an iso-type control antibody (Control ab), an antibody against GP1b�� (anti-GP1b�� ab) ... CXC chemokines Leukocyte extravasation into the liver parenchyma has been reported to be directed by secreted CXC chemokines (Li et al., 2004).

We observed that the hepatic levels of CXC chemokines in sham animals were low but detectable (Figure 7, n=6�C8). In contrast, ligation of the common bile duct markedly increased hepatic levels of MIP-2 and KC (Figure 7, P<0.05 vs sham, n=6�C8). Interestingly, pretreatment with the anti-GP-1b�� ab reduced BDL-provoked expression of MIP-2 and KC. That is, depletion of platelets attenuated formation of CXC chemokines by more than 63% in cholestatic mice (Figure 7). Similarly, administration of the anti-P-selectin ab significantly reduced BDL-induced expression of MIP-2 by 73% and of KC by 66% (Figure 7, P<0.05 vs Control ab+BDL, n=6�C8). Figure 7 Hepatic levels of (a) macrophage inflammatory protein-2 (MIP-2) and (b) cytokine-induced neutrophil chemoattractant (KC) 12h after ligation of the common bile duct. Mice were pretreated i.

v. with an iso-type control antibody (Control ab), an … Discussion and conclusions Surgical and endoscopic decompression is the principal treatment of biliary obstruction but may not be sufficient to prevent development of hepatic injury and septic complications. Thus, mechanistic studies are needed to delineate the pathophysiology of cholestasis-induced liver damage. This study Brefeldin_A demonstrates for the first time an important role of platelets in supporting BDL-mediated leukocyte recruitment in the liver.