Aspirin-Triggered 15-Epi-Lipoxin A₄ and Novel Lipoxin B₄ Stable Analogs Inhibit Neutrophil-Mediated Changes in Vascular Permeability

Abstract

Leukocyte-dependent endothelial cell injury leads to changes in vascular permeability, edema, and further release of chemoattractants.¹ The hallmark of reperfusion injury is considered to be diminished barrier function of vascular endothelium. Leukotriene B₄ (LTB₄)‡ is among the most potent neutrophil stimuli and thus participates in tissue injury via recruiting PMN in pathophysiologic scenarios.² Lipoxins are trihydroxytetraene-containing eicosanoids that are, among other in vivo sites, also generated within vascular lumen primarily by platelet-leukocyte interactions by pathways that are activated during multicellular responses such as inflammation, atherosclerosis, and thrombosis (as reviewed in Serhan).³ Recently, aspirin was shown to trigger the biosynthesis of a new group of compounds termed 15-epi-LX or aspirin-triggered lipoxins that may contribute to some of the beneficial actions ascribed to aspirin.3 Thus, these two LX branches involving cell-cell interactions within the eicosanoid cascade appear to produce “endogenous stop signals,” whereas the 5-lipoxygenase pathway generates leukotrienes, which are proinflammatory mediators.