Inhibition of platelet-activating factor, intercellular adhesion molecule 1 and platelet endothelial cell adhesion molecule 1 reduces experimental pancreatitis-associated gut endothelial barrier dysfunction

Br J Surg. 1999 Mar;86(3):411-6. doi: 10.1046/j.1365-2168.1999.01028.x.


Background: Endothelial barrier dysfunction is a critical link in the development of tissue injury and organ dysfunction, via upregulation and exposure of adhesion molecules, intercellular signals and leucocyte-endothelial cell interactions. Inhibitors of inflammatory mediators and receptors have been suggested as a means of downregulating the cascade of both local and systemic inflammation.

Methods: The potential therapeutic inhibition of platelet-activating factor (PAF), intercellular adhesion molecule (ICAM) 1 and platelet endothelial cell adhesion molecule (PECAM) 1 was investigated in pancreatitis-associated gut endothelial dysfunction in rats, by treatment with a PAF antagonist (lexipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM1-Mb) and PECAM (anti-PECAMA1-Mb). Alterations in gut endothelial barrier dysfunction and leucocyte recruitment, and systemic levels of interleukins were evaluated.

Results: Plasma exudation measured by the albumin leakage index and tissue leucocyte recruitment in the distal small intestine and colon increased significantly 12 h after induction of pancreatitis and treatment with saline. These alterations were to varying degrees counteracted by treatment with lexipafant, anti-ICAM1-Mb or anti-PECAM1-Mb. Alterations in levels of interleukin (IL) 1 paralleled the changes in gut endothelial barrier dysfunction and leucocyte trapping.

Conclusion: Treatment with lexipafant and monoclonal antibodies against ICAM-1 or PECAM-1 reduced the severity of pancreatitis-associated gut endothelial dysfunction, and decreased systemic concentrations of IL-1 and local leucocyte recruitment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillaries
  • Endothelium, Vascular / metabolism
  • Gastrointestinal Diseases / metabolism
  • Gastrointestinal Diseases / prevention & control*
  • Imidazoles / pharmacology*
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Interleukins / metabolism
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Leukocytes
  • Lymphocyte Activation
  • Male
  • Pancreatitis / complications
  • Pancreatitis / metabolism
  • Pancreatitis / prevention & control*
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Imidazoles
  • Interleukins
  • Platelet Activating Factor
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Leucine
  • lexipafant