Pulmonary injury after intestinal ischemia and reperfusion injury: effects of treatment with lexipafant, a PAF antagonist

Full text

Intestinal ischemia and reperfusion (I/R) can lead to the development of pulmonary injury characterized by increased leakage of macromolecules over pulmonary capillaries, and leukocyte sequestration. Important mediators of I/R-associated injury include polymorphonuclear granulocytes (PMNs) and platelet-activating factor (PAF). PMNs exposed to PAF demonstrate an increased expression of adhesion molecules, leading to increased PMN-endothelial cell interactions. Once adherent, PAF can further activate PMNs to increased respiratory burst activity and degranulation, leading to damage of the pulmonary endothelium. In the present study, we found an increased leakage of radiolabeled human serum albumin in the lungs of rats after 30 min intestinal ischemia (by clamping of the superior mesenteric artery) followed by 3 and 12 h reperfusion. The increased leakage could at least in part be prevented by lexipafant, a potent PAF-antagonist, administered intraperitoneally, after the onset of reperfusion. Pulmonary myeloperoxidase (MPO) content also increased after intestinal I/R, indicating PMN sequestration through the pulmonary endothelium. In conclusion, pulmonary injury in the rat, characterized by increased leakage of radiolabeled albumin over the endothelial barrier, correlated well with increased pulmonary MPO-content, implying the involvement of PMNs in the pathogenesis of remote organ injury after experimental intestinal I/R. Treatment with a PAF antagonist, lexipafant, decreased the severity of pulmonary damage. The potential clinical use of PAF-antagonists in I/R-associated pulmonary injury remains to be evaluated.