title: P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis.
abstract: 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 µg/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) µg/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) µg/l; P = 0·069). Intravital fluorescence microscopy revealed that anti-P-selectin antibody inhibited leucocyte rolling completely in postcapillary venules of the inflamed pancreas.
  
  
  CONCLUSIONS
  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.
authors: Department of Clinical Sciences, Malmö, Section of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
authors: H
authors: H
authors: Hartman
authors: A
authors: A
authors: Abdulla
authors: D
authors: D
authors: Awla
authors: B
authors: B
authors: Lindkvist
authors: B
authors: B
authors: Jeppsson
authors: H
authors: H
authors: Thorlacius
authors: S
authors: S
authors: Regnér
mesh_terms: D000208:Acute Disease; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D054426:Chemokine CXCL2 / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D004727:Endothelium / Q000502:physiology; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000037:antagonists & inhibitors / Q000502:physiology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D013656:Taurocholic Acid / Q000633:toxicity; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D002756:Cholagogues and Choleretics; D016207:Cytokines; D019007:P-Selectin; D013656:Taurocholic Acid; D014362:Trypsinogen; D009195:Peroxidase