P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis

Background: The adhesive mechanisms regulating leucocyte-endothelium interactions in the pancreas remain elusive, but selectins may play a role. This study examined the molecular mechanisms mediating leucocyte rolling along the endothelium in the pancreas and the therapeutic potential of targeting the rolling adhesive interaction in acute pancreatitis (AP). Methods: Pancreatitis was induced by retrograde infusion of 5 per cent sodium taurocholate into the pancreatic duct, repeated intraperitoneal administration of caerulein (50 mu g/kg) or intraperitoneal administration of L-arginine (4 g/kg) in C57BL/6 mice. A control and a monoclonal antibody against P-selectin were administered before and after induction of AP. Serum and tissue were sampled to assess the severity of pancreatitis, and intravital microscopy was used to study leucocyte rolling. Results: Taurocholate infusion into the pancreatic duct increased the serum level of trypsinogen, trypsinogen activation, pancreatic neutrophil infiltration, macrophage inflammatory protein (MIP) 2 formation and tissue damage. Immunoneutralization of P-selectin decreased the taurocholate-induced increase in serum trypsinogen (median (range) 17.35 (12.20-30.00) versus 1.55 (0 .60-15.70) mu g/l; P = 0.017), neutrophil accumulation (4.00 (0.75-4.00) versus 0 . 63 (0-3.25); P = 0.002) and tissue damage, but had no effect on MIP-2 production (14.08 (1.68-33.38) versus 3.70 (0.55-51.80) pg/mg; P = 0.195) or serum trypsinogen activating peptide level (1.10 (0.60-1.60) versus 0.45 (0-1.80) mu g/l; P = 0.069). Intravital fluorescence microscopy revealed that anti-P-selectin antibody inhibited leucocyte rolling completely in postcapillary venules of the inflamed pancreas. Conclusion: Inhibition of P-selectin protected against pancreatic tissue injury in experimental pancreatitis. Targeting P-selectin may be an effective strategy to ameliorate inflammation in AP.