Advertisement

International Journal of Pancreatology

, Volume 25, Issue 1, pp 45–52 | Cite as

Treatment with lexipafant ameliorates the severity of pancreatic microvascular endothelial barrier dysfunction in rats with acute hemorrhagic pancreatitis

  • Xiangdong Wang
  • Zhengwu Sun
  • Anna Börjesson
  • Pernille Haraldsen
  • Malin Aldman
  • Xiaoming Deng
  • Per Leveau
  • Roland Andersson
Article

Summary

Conclusion: Treatment with lexipafant reduced the severity of pancreatitis-associated endothelial barrier compromise, also associated with a decrease in systemic concentrations of interleukin (IL) 1. Thus, the present findings imply that platelet-activating factor (PAF) may play an important role in the pathogenesis of pancreatic endothelial dysfunction by signaling and triggering the production and release of certain cytokines.

Background: Pancreatic capillary endothelial barrier dysfunction is an initial and characteristic feature of acute pancreatic injury and pancreatitis. PAF, a proinflammatory mediator and an intercellular signaling substance, has been considered to be involved in the inflammatory reaction and the systemic endothelial dysfunction of acute pancreatitis.

Methods: The development of pancreatic capillary endothelial barrier dysfunction was monitored by tissue edema and exudation of plasma albumin into the interstitium, 3 and 12 h after induction of acute pancreatitis by intraductal infusion of 5% sodium taurodeoxycholate in rats. Pancreatic leukocyte recruitment was reflected by measuring myeloperoxidase activity. Serum levels of IL-1β and IL-6 were determined by an enzyme-linked immunosorbent assay (ELISA).

Results: Pretreatment with lexipafant, a potent PAF receptor antagonist, significantly reduced the pancreatitis-induced increase in pancreatic endothelial barrier dysfunction, pancreatic leukocyte recruitment, and serum levels of IL-1β, although a difference persisted between animals with sham operation and pancreatitis.

Key Words

Pancreatitis endothelium permeability interleukines leukocytes platelet-activating factor lexipafant 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kingsnorth AN. Platelet-activating factor. Scand J Gastroenterol 1996; 31: S28-S31.CrossRefGoogle Scholar
  2. 2.
    Kingsnorth AN, Galloway SW, Formela LJ. Randomized, double-blind phase II trial of lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br J Surg 1995; 82: 1414–1420.PubMedCrossRefGoogle Scholar
  3. 3.
    McKay CJ, Curran F, Sharples C, Baxter JN, Imrie CW. Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis. Br J Surg 1997; 84: 1239–1243.PubMedCrossRefGoogle Scholar
  4. 4.
    Konturek SJ, Dembinski A, Konturek PJ, Warzecha Z, Jaworek-J, Gustaw P, et al. Role of platelet activating factor in pathogenesis of acute pancreatitis in rats. Gut 1992; 33: 1268–1274.PubMedCrossRefGoogle Scholar
  5. 5.
    Emanuelli G, Montrucchio G, Gaia E, Dughera L, Corvetti G, Gubetta L. Experimental acute pancreatitis induced by platelet activating factor in rabbits. Am J Pathol 1989; 134: 315–326.PubMedGoogle Scholar
  6. 6.
    Galloway SW, Kingsnorth AN. Lung injury in the microembolic model of acute pancreatitis and amelioration by lexipafant (BB-882), a platelet-activating factor antagonist. Pancreas 1996; 13: 140–146.CrossRefGoogle Scholar
  7. 7.
    Deng XM, Wang XD, Andersson R. Endothelial barrier resistance in multiple organs after septic and nonseptic challenges in the rats. J Appl Physiol 1995; 78: 2052–2061.PubMedGoogle Scholar
  8. 8.
    Sanfey H, Camerron JL. Increased capillary permeability and early lesion in acute pancreatitis. Surgery 1984; 96: 485–491.PubMedGoogle Scholar
  9. 9.
    Kerner T, Vollmar B, Menger MD, Waldner H, Messmer K. Determinants of pancreatic microcirculation in acute pancreatitis in rats. J Surg Res 1996; 62: 165–171.CrossRefGoogle Scholar
  10. 10.
    Wang XD, Andersson R. The role of endothelial cells in the systemic inflammatory response syndrome and multiple system organ failure. Eur J Surg 1995; 161: 703–713.PubMedGoogle Scholar
  11. 11.
    Wang XD, Deng XM, Haraldsen P, Andersson R, Ihse I, Antioxidant and calcium channel blockers counteract endothelial barrier injury induced by acute pancreatitis in the rat. Scand J Gastroenterol 1995; 30: 1129–1136.PubMedCrossRefGoogle Scholar
  12. 12.
    Hirano T. Peptide leukotriene receptor antagonist diminishes pancreatic edema formation in rats with cerulin-induced acute pancreatitis. Scand J Gastroenterol 1997; 32: 84–88.PubMedCrossRefGoogle Scholar
  13. 13.
    Menger MD, Bonkhoff H, Vollmar B. Ischemia-reperfusion-induced pancreatic microvascular injury. An intravital fluorescence microscopic study in rats. Dig Dis Sci 1996; 41: 823–830.CrossRefGoogle Scholar
  14. 14.
    Hoffmann TF, Waldner H, Messmer K. The bradykinin antagonist CP-0597 can limit the progression of postischemic pancreatitis. Immunopharmacology 1996; 33: 243–246.CrossRefGoogle Scholar
  15. 15.
    Siflinger-Birnboim A, Malik AB. Regulation of endothelial permeability by second messengers. New Horiz 1996; 4: 87–98.Google Scholar
  16. 16.
    Chao W, Olson MS. Platelet-activating factor: receptors and signal transduction. Biochem J 1993; 292: 617–627.PubMedGoogle Scholar
  17. 17.
    Haraldsen G, Kvale D, Lien B, Farstad IN, Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercell- u-lar adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human intestinalGoogle Scholar

Copyright information

© Humana Press Inc 1999

Authors and Affiliations

  • Xiangdong Wang
    • 1
  • Zhengwu Sun
    • 1
  • Anna Börjesson
    • 1
  • Pernille Haraldsen
    • 1
  • Malin Aldman
    • 1
  • Xiaoming Deng
    • 1
  • Per Leveau
    • 1
  • Roland Andersson
    • 1
  1. 1.Department of SurgeryLund University HospitalLundSweden

Personalised recommendations