P-selectin inhibition reduces severity of acute experimental pancreatitis.
BACKGROUND
Acute pancreatitis (AP) is characterized by disturbed pancreatic microcirculation with tissue necrosis. Platelet and leukocyte activation contributes to microcirculatory disorders and inflammatory tissue infiltration. P-selectin mediates the adhesion of both activated platelets and leukocytes to the vessel wall. The aim of this study was to investigate the effect of P-selectin inhibition by monoclonal antibodies (AB) on experimental AP.


METHODS
AP was induced in rats by glycodeoxycholic acid (GDOC) intraductally and by cerulein infusion. Animals were divided into 4 groups: (1) severe AP (GDOC); (2) severe AP + platelet inhibition (GDOC + selectin AB); (3) control (Ringer); (4) control + platelet inhibition (Ringer + selectin AB). 24 h after AP induction, histology and serum (amylase, thromboxane A2) were evaluated (6 animals per group). In additional 12 animals of each group, platelet and leukocyte activation as well as erythrocyte flow patterns were evaluated by intravital microscopy 12 h after AP induction.


RESULTS
AP induction caused significant tissue inflammation and necrosis with increased amylase and thromboxane levels. Prophylactic inhibition of P-selectin reduced tissue inflammation and necrosis significantly. Severe AP led to significantly more adherent platelets and leukocytes in capillaries and venules. In contrast, antibody-treated animals showed significantly reduced platelet-endothelium interaction compared with untreated AP animals. Antibody application in control animals without AP did not induce any changes compared with healthy control animals.


CONCLUSIONS
Inhibition of P-selectin reduces tissue damage in experimental AP. This is associated with a reduction in platelet- and leukocyte-endothelium interaction and an improvement in pancreatic microcirculation.
Hackert
Thilo
T
Department of Surgery and Experimental Surgery, University of Heidelberg, Heidelberg, Germany. thilo_hackert@med.uni-heidelberg.de
Sperber
Rasmus
R
Hartwig
Werner
W
Fritz
Stefan
S
Schneider
Lutz
L
Gebhard
Martha-Maria
MM
Werner
Jens
J
D000681:Amylases / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D006002:Glycodeoxycholic Acid; D008297:Male; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000276:immunology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000097:blood
D000911:Antibodies, Monoclonal; D019007:P-Selectin; D006002:Glycodeoxycholic Acid; D013928:Thromboxane A2; D009195:Peroxidase; D000681:Amylases