15-Lipoxygenase products as leukotriene antagonists: therapeutic potential in glomerulonephritis

In the first few hours following immune complex deposition and complement-mediated neutrophil (PMN) infiltration, glomerular generation rates of the arachidonate 5-lipoxygenase (5-LO) derivatives leukotrienes (LT) C4, D4, and B4 are stimulated markedly. These LTs exert effects on glomerular functions which include reduction in the glomerular ultrafiltration coefficient and glomerular filtration rates, exacerbation of proteinuria, and amplification of PMN-provoked glomerular damage through LTB4-induced PMN chemotaxis, adhesion, and activation. Following this early burst, glomerular LT synthesis is suppressed, macrophages replace PMNs, and glomerular generation of 15-S-hydroxyeicosatetraenoic acid [15-(S)-HETE], a 15-lipoxygenase derivative of arachidonic acid and a precursor molecule for lipoxin (LX) biosynthesis, increases progressively over the ensuing days to weeks. Here, we summarize evidence supporting the notion that the activation of the 15-LO pathway in the wake of early 5-LO activity is a specific counter-inflammatory signal which limits and antagonizes the proinflammatory actions of leukotrienes.