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 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.


CONCLUSIONS
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.
Wang
X
X
Department of Surgery, Lund University Hospital, Sweden.
Sun
Z
Z
Börjesson
A
A
Andersson
R
R
D000818:Animals; D002196:Capillaries; D004730:Endothelium, Vascular / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000378:metabolism / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007962:Leukocytes; D008213:Lymphocyte Activation; D008297:Male; D010195:Pancreatitis / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007093:Imidazoles; D007378:Interleukins; D010972:Platelet Activating Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007930:Leucine; C103289:lexipafant