Leukotrienes and lipoxins: lipoxygenase-derived modulators of leukocyte recruitment and vascular tone in glomerulonephritis

With the gradual elucidation of the cellular and molecular events that underpin the inflammatory process, the pathogenetic complexities of glomerulonephritis are slowly being unravelled. Lipoxygenase-derived eicosanoids play important counter-regulatory roles within inflamed glomeruli. Leukotrienes, derived from the 5-lipoxygenase pathway, are potent stimuli for leukocyte infiltration, intrarenal vasoconstriction, and mesangial cell contraction in many forms of experimental glomerulonephritis and probably in human disease. The recruitment of 12- and 15-lipoxygenase pathways, particularly during cell-cell interactions, promotes the formation of lipoxins. The latter compounds antagonize many leukotriene effects, attenuate neutrophil recruitment, and are potential 'braking signals' within the inflammatory cascade that promote resolution of inflammation. The generation and metabolism of leukotrienes and lipoxins is regulated independently, and each family of eicosanoids mediates its biological activities through distinct cell surface receptors and signal transduction pathways. Leukotriene biosynthesis inhibitors and leukotriene receptor antagonists are protective in several experimental models of glomerulonephritis. Initial studies with lipoxins and synthetic lipoxin stable analogues suggest that it may be possible to harness this and other putative anti-inflammatory system for therapeutic gain.