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

Abstract

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.