Lipoxygenase metabolites modulate vascular-derived platelet activating factor production following endotoxin challenge

Endotoxin promotes the production of potent pro-inflammatory lipid mediators, such as platelet activating factor (PAF) and eicosanoids, which contribute to the pathophysiology of endotoxic shock. Endothelial cells are both a target for and producers of these lipid mediators so it is vital to understand the pathways leading to their production in these cells. Previous research suggested a positive feedback loop between eicosanoids and PAF during endotoxemia. This study sought to determine if eicosanoids derived from the 15-lipoxygenase (15-LOX1) pathway can modulate the biosynthesis of PAF in cultured bovine aortic endothelial cells (BAEC) following endotoxin stimulation. Endotoxin stimulation increased the production of 15-LOX1-derived eicosanoids prior to PAF in primary BAEC. Exogenous addition of specific 15-LOX1 eicosanoids, as well as overexpression of 15-LOX1 in endotoxin-stimulated BAEC, further increased the endotoxin-induced production of PAF. Whereas increased expression of 15-LOX1 activity can further exacerbate endotoxin-induced PAF biosynthesis, inhibition of 15-LOX1 activity is not capable of abrogating the initial onset of endotoxin-induced PAF production. The results indicate that 15-LOX1 activity is not necessary for the initial induction of PAF following endotoxin stimulation. There may exist, however, a role for elevated 15-LOX1 activity in further escalating the extent of PAF biosynthesis in BAEC during endotoxic shock. Determining factors that can potentiate endotoxin-induced vascular dysfunction may lead to the development of novel therapeutic targets to diminish the pathophysiological effects of endotoxic shock.