, 1999; Klintman et al., 2004; Laschke et al., 2007). Moreover, considering our findings that inhibition of P-selectin decreases both platelet and leukocyte adhesion LY188011 in BDL mice, targeting P-selectin may be of particular value in this case, because both platelets and leukocytes may cause tissue damage in cholestatic liver injury. In this context, it is important to underline that the inhibitory effect of the anti-P-selectin ab on BDL-induced accumulation of leukocytes in sinusoids is likely to be an indirect effect, that is convincing data have shown that P-selectin is not expressed in sinusoidal endothelium (Steinhoff et al., 1993; Essani et al., 1998; Massaguer et al., 2002) and intravital observations have shown that leukocytes do not roll in sinusoids (Wong et al., 1997; Klintman et al.
, 2004). Notably, we observed that inhibition of P-selectin reduced sinusoidal accumulation of platelets by 37%, which was similar in magnitude to the 48% reduction in sinusoidal recruitment of leukocytes. In combination, it may be suggested that P-selectin-mediated accumulation of leukocytes in hepatic sinusoids is platelet dependent. P-selectin is not only expressed in Weibel�CPalade bodies of endothelial cells but also in ��-granules of platelets (Isenberg et al., 1986). In fact, numerous studies have demonstrated that adhesive interactions between platelets and leukocytes are supported by platelet P-selectin binding to P-selectin glycoprotein ligand-1 expressed on leukocytes (Hamburger and McEver, 1990; Rinder et al., 1991; Abou-Saleh et al., 2005).
The detailed role of P-selectin remains elusive and may be multiple. For example, adherent platelets on endothelial cells may serve as an adhesive P-selectin substrate and directly capture circulating leukocytes on the endothelium. However, platelets and leukocytes can also interact via P-selectin/P-selectin glycoprotein ligand-1 in the circulation resulting in aggregate formation, which might subsequently be trapped mechanically in the narrow liver sinusoids. In addition, leukocytes attached to platelets become activated and upregulate surface expression of CD11b (Pitchford et al., 2004), which may prime leukocytes for firm adhesion in sinusoids and tissue infiltration. Activation and tissue navigation of leukocytes are coordinated by secreted chemokines (Campbell et al., 2003). The CXC chemokines, MIP-2 and KC, are considered to attract predominately neutrophils and have been demonstrated Anacetrapib to regulate leukocyte recruitment in septic liver injury (Li et al., 2004). Herein, we observed that the hepatic formation of MIP-2 and KC was greatly increased after ligation of the common bile duct.