Regulation of neutrophil trafficking by the lipid mediators of inflammation

Excerpt

The lipid mediators of inflammation include platelet-activating factor (PAF) and several classes of metabolites of arachidonic acid derived from the cyclooxygenase (prostaglandins and thrombox-anes) and lipoxygenase pathways, such as leukotrienes (LTs) and lipox-ins. Of these lipid mediators, LTs and PAF are potent agonists of leukocytes and endothelial cells and show important proinflammatory properties. Several elegant studies have recently provided strong support for a role of one of these mediators, LTB₄, in animal models of rheumatoid arthritis [1‐3]. Interestingly, LTB₄, LTC₄/LTD₄ and PAF are concomitantly generated at the blood–endothelium interface when neutrophils bind to activated endothelial cells at inflammatory sites in vivo and are exposed to a chemoattractant. The hypothesis explored in this project is that the three classes of lipid mediators collectively and synergistically act to promote and facilitate neutrophil extravasation and accumulation at inflammatory sites. The hypothesis also implicates that, given the high level of redundancy in the abilities of the three lipid mediators to activate neutrophils and endothelial cells, the blockade of one of these mediators can only have a modest and incomplete inhibitory effect on neutrophil extravasation. …