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

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 finding s imply that platelet-activating factor (PAF) may play an important role in the pathogenesis of pancreatic endothelial dysfunction by signaling and tr iggering the production and release of certain cytokines. Background: Pancreatic capillary endothelial barrier dysfunction is an init ial 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 sys temic endothelial dysfunction of acute pancreatitis. Methods: The development of pancreatic capillary endothelial barrier dysfun ction was monitored by tissue edema and exudation of plasma albumin into th e interstitium, 3 and 12 h after induction of acute pancreatitis by intradu ctal infusion of 5% sodium taurodeoxycholate in rats. Pancreatic leukocyte recruitment was reflected by measuring myeloperoxidase activity. Serum leve ls of IL-1 beta and IL-6 were determined by an enzyme-linked immunosorbent assay (ELISA). Results: Pretreatment with lexipafant, a potent PAF receptor antagonist, si gnificantly reduced the pancreatitis-induced increase in pancreatic endothe lial barrier dysfunction, pancreatic leukocyte recruitment, and serum level s of IL-IP, although a difference persisted between animals with sham opera tion and pancreatitis.