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

Background: Endothelial barrier dysfunction is a critical link in the devel opment of tissue injury and organ dysfunction, via upregulation and exposur e of adhesion molecules, intercellular signals and leucocyte-endothelial ce ll interactions. Inhibitors of inflammatory mediators and receptors have be en suggested as a means of downregulating the cascade of both local and sys temic inflammation. Methods: The potential therapeutic inhibition of platelet-activating factor (PAF), intercellular adhesion molecule (ICAM) 1 and platelet endothelial c ell adhesion molecule (PECAM) 1 was investigated in pancreatitis-associated gut endothelial dysfunction in rats, by treatment with a PAF antagonist (l exipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM1 -Mb) and PECAM (anti-PECAM1-Mb). Alterations in gut endothelial barrier dys function and leucocyte recruitment, and systemic levels of interleukins wer e evaluated. Results: Plasma exudation measured by the albumin leakage index and tissue leucocyte recruitment in the distal small intestine and colon increased sig nificantly 12 h after induction of pancreatitis and treatment with saline. These alterations were to varying degrees counteracted by treatment with le xipafant, anti-ICAM1-Mb or anti-PECAM1-Mb. Alterations in levels of interle ukin (IL) 1 paralleled the changes in gut endothelial barrier dysfunction a nd leucocyte trapping. Conclusion: Treatment with lexipafant and monoclonal antibodies against ICA M-1 or PECAM-1 reduced the severity of pancreatitis-associated gut endothel ial dysfunction, and decreased systemic concentrations of IL-1 and local le ucocyte recruitment.