title: Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion.
abstract: BACKGROUND
  The serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte-endothelial cell interactions after ischemia and reperfusion.
  
  
  METHODS
  The effects of aprotinin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion.
  
  
  RESULTS
  Intravenous bolus administration of aprotinin treatment (20,000 U/kg) significantly reduced leukocyte rolling from 55 +/- 8 to 17 +/- 3 cells/min (p < 0.01) and adherent cells from 12 +/- 2 to 7 +/- 1.4 cells (p < 0.05) along the venous endothelium of the rat mesentery after thrombin activation. In addition, aprotinin pretreatment significantly inhibited transmigration of leukocytes from 11.3 +/- 1.2 to 6.0 +/- 1.1 cells (p < 0.05) through the microvascular endothelial wall. Similarly, aprotinin decreased leukocyte-endothelium interaction after hemorrhagic shock. Moreover, immunohistochemistry demonstrated that aprotinin significantly attenuated P-selectin expression by the intestinal vascular endothelium. CONCLUSIONS. Our data demonstrate that aprotinin potently inhibits recruitment of leukocytes in the microvasculature by interfering with endothelial cell-polymorphonuclear neutrophil interaction, and is a potent endothelial protective agent in clinically relevant doses. Thus, aprotinin pretreatment may be useful for primary prevention of inflammatory tissue injury mediated by ischemia-reperfusion injury such as shock, trauma, open heart operation, or other extensive vascular surgical procedures.
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Diethard
authors.initials: D
authors.lastname: Pruefer
authors.forename: Joachim
authors.initials: J
authors.lastname: Makowski
authors.forename: Manfred
authors.initials: M
authors.lastname: Dahm
authors.forename: Stefan
authors.initials: S
authors.lastname: Guth
authors.forename: Hellmut
authors.initials: H
authors.lastname: Oelert
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
mesh_terms: D000818:Animals; D007611:Aprotinin / Q000008:administration & dosage / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D006470:Hemorrhage / Q000503:physiopathology*; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008643:Mesentery; D008833:Microcirculation / Q000187:drug effects; D019007:P-Selectin / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
chemical_list: D019007:P-Selectin; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin; D013917:Thrombin