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Effect of a platelet-activating factor antagonist on pancreatitis-associated gut barrier dysfunction in rats
1Department of Surgery, Lund University Hospital, Sweden.
Insights
Platelet-activating factor (PAF) contributes to acute pancreatitis and organ injury. A PAF antagonist, lexipafant, prevented gut barrier dysfunction and reduced bacterial translocation in animal models.
Area of Science:
- Gastroenterology
- Pathophysiology
- Pharmacology
Background:
- Platelet-activating factor (PAF) is implicated in acute pancreatitis and associated organ damage.
- Gut barrier dysfunction is a key complication of acute pancreatitis.
Purpose of the Study:
- To evaluate the efficacy of the PAF antagonist, lexipafant, in preventing gut barrier dysfunction in acute pancreatitis.
- To assess lexipafant's impact on intestinal permeability, bacterial translocation, and endothelial integrity.
Main Methods:
- Acute pancreatitis was induced in animal models via intraductal sodium taurocholate infusion.
- The study measured gut origin sepsis, intestinal permeability, albumin leakage, hematocrit, lipase, and calcium levels.
- Effects of lexipafant pretreatment were compared to saline-treated controls.
Main Results:
- Lexipafant significantly reduced pancreatic endothelial permeability and albumin leakage.
- The PAF antagonist counteracted alterations in hematocrit, lipase, and calcium levels.
- Lexipafant decreased bacterial translocation and microthrombosis in intestinal villi.
Conclusions:
- PAF plays a role in pancreatitis-associated intestinal dysfunction and distant organ injury.
- PAF antagonists, like lexipafant, show potential in preventing gut barrier dysfunction in acute pancreatitis.
- Targeting PAF may be a therapeutic strategy for managing pancreatitis complications.
Abstract:
Platelet-activating factor (PAF) may play a critical and primary role in the pathogenesis of acute pancreatitis and pancreatitis-associated distant organ injury. The present study evaluated the effect of a PAF antagonist, lexipafant (an (S)-4-methyl-2[methyl-imidazo[4,5-c]pyridin-1-ylmethyl)-benzene sulphonyl]-amino]pentanoic acid ethyl ester, BB-882; British Biotech Ltd.), on the potential prevention of gut barrier dysfunction, by measuring gut origin sepsis, bidirectional permeability of the intestinal barrier, and pancreatic capillary endothelial barrier integrity, in acute pancreatitis induced by intraductal infusion of 5% sodium taurodeoxycholate. Pancreatic endothelial permeability significantly increased in animals with acute pancreatitis, whereas pretreatment with lexipafant had a preventive effect (p < 0.05 vs. pancreatitis with saline). Similarly, alterations noted in hematocrit and plasma levels of lipase and calcium were counteracted by the PAF antagonist. It also prevented the increase in albumin leakage from blood to the mucosal interstitium and from blood to the intestinal lumen in acute pancreatitis. Albumin passage from the gut lumen to blood in animals with pancreatitis pretreated with saline increased from 3 h and on, and lexipafant prevented alterations in mucosal epithelial permeability. Bacterial translocation was commonly seen in pancreatitis, whereas only a few positive cultures were observed in pancreatitis animals given lexipafant. Microthrombosis in intestinal villi seemed less frequent after lexipafant pretreatment. We conclude that (a) PAF may play a role in the pathogenesis of pancreatitis-associated intestinal dysfunction, (b) PAF may be involved in the development of distant organ dysfunction by triggering endothelial barrier dysfunction, and (c) PAF antagonists may provide potential agents for preventing pancreatitis-associated gut barrier dysfunction.