In contrast, pre-treatment with 0.2 mg?kg?1 of simvastatin decreased BDL-induced leukocyte adhesion in the hepatic postsinusoidal venules by 73% (Figure 3B, P < 0.05 vs. vehicle+BDL, n = 5). Moreover, simvastatin significantly inhibited BDL-induced leukocyte adhesion in sinusoids by 27% (Figure 3C, P < 0.05 vs. vehicle+BDL, n = 5). Hepatic levels of MPO were used to determine http://www.selleckchem.com/products/Calcitriol-(Rocaltrol).html the global accumulation of neutrophils, which constitute the predominant leukocyte subset in the liver early after BDL induction (Georgiev et al., 2008). It was found that BDL increased MPO levels by more than threefold compared with sham mice (Figure 3D, P < 0.05 vs. Sham, n = 5). Administration of 0.2 mg?kg?1 of simvastatin significantly reduced the hepatic levels of MPO in BDL mice by 67% (Figure 3D, P < 0.05 vs.

vehicle+BDL, n = 5). Representative photos of leukocyte-endothelium interactions in the hepatic microcirculation are shown in Figure 4. In addition, the percentage of non-perfused sinusoids was increased in BDL mice (Figure 5, P < 0.05 vs. Sham, n = 5) but this was decreased in the simvastatin-treated mice (Figure 5, P < 0.05 vs. vehicle+BDL, n = 5). Figure 5 Sinusoidal perfusion failure 12 h after ligation of the common bile duct. Mice were treated. with vehicle and simvastatin (Sim, 0.2 and 0.02 mg?kg?1, i.p.) prior to bile duct ligation (BDL). Sham animals received only PBS. Data represent ... Figure 4 Representative pictures of intravital microscopy of liver tissue. Leukocytes in postsinusoidal venules and sinusoids are indicated with white arrows.

Pictures were taken 12 h after ligation of the common bile duct. Mice were injected (i.p.) with either … Figure 3 Leukocyte rolling (A) and adhesion in postsinusoidal venules (B) and leukocyte adhesion in sinusoids (C) and levels of MPO (D) 12 h after ligation of the common bile duct. Mice were treated with vehicle and simvastatin (Sim, 0.2 and 0.02 mg?kg … CXC chemokines Hepatic levels of CXC chemokines in control animals were low but detectable (Figure 6, n = 5). Ligation of the common bile duct increased hepatic levels of MIP-2 and KC significantly (Figure 6, P < 0.05 vs. Sham, n = 5). Pre-treatment with 0.2 mg?kg?1 simvastatin decreased BDL-induced formation of MIP-2 and KC (Figure 6, P < 0.05 vs. vehicle+BDL, n = 5). Thus, simvastatin attenuated formation of MIP-2 and KC by 82% and 37%, respectively, in cholestatic mice.

Figure 6 Hepatic levels of MIP-2 (A) and KC (B) 12 h after ligation of the common bile duct. Mice were treated with vehicle and simvastatin (Sim, 0.2 and 0.02 mg?kg?1, i.p.) prior to bile duct ligation (BDL). Sham Brefeldin_A animals received only PBS. Data … Therapeutic effect of simvastatin In order to test the therapeutic potential of simvastatin on cholestatic liver injury, separate mice were treated with 0.2 mg?kg?1 simvastatin 2 h after BDL induction.