Beneficial effects of lexipafant, a PAF antagonist on gut barrier dysfunction caused by intestinal ischemia and reperfusion in rats

BACKGROUND: Platelet-activating factor (PAF) may play a pivotal role in the pathogenesis of intestinal ischemic injury. METHODS: The potential role of PAF in intestinal ischemia and reperfusion (I/R) and the development of gut endothelial and epithelial barrier dysfunction and distant organ injury were investigated by pretreatment with a PAF antagonist, lexipafant. Bidirectional permeability of the intestinal barrier, enteric bacterial translocation, protease-antiprotease balance and mucosal histology, and also changes in pulmonary and liver endothelial barrier permeability were measured following intestinal ischemia for 40 min with 6 h of reperfusion in rats. RESULTS: Intestinal mucosal endothelial and epithelial permeabilities significantly increased in animals with I/R. Lexipafant prevented the increase in albumin leakage from blood to the mucosal interstitium and the intestinal lumen during reperfusion, and the mucosal albumin leakage from the gut lumen to blood during I/R. Bacterial translocation was frequently noted in animals with I/R, while only a few positive cultures were obtained in animals with I/R administered lexipafant. Less leakage of fluorescein isothiocyanate dextran 70,000 into the interstitial space and gut lumen in I/R animals with lexipafant pretreatment was found under fluorescein microscopy. Lexipafant also partly prevented C1 inhibitor, prekallikrein, and factor X consumption in I/R animals and partly prevented changes in pulmonary and liver albumin leakage. CONCLUSIONS: PAF seems to play an important role in I/R-associated intestinal dysfunction and the development of distant organ dysfunction, probably by triggering endothelial and epithelial barrier dysfunction. Furthermore, PAF seems to be partly involved in activation of the protease-antiprotease system. The use of PAF antagonists may provide a mode of treatment against I/R-associated organ dysfunction.