Role of leukotrienes and lipoxygenases in glomerular injury

The 5-lipoxygenated metabolites of arachidonic acid, the leukotrienes, are increasingly recognized as major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis. Generation of these metabolites is largely by infiltrating leukocytes, but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In several animal models of glomerulonephritis and other renal pathologic states, leukotrienes have been shown to exert adverse effects in the glomerulus. Leukotriene B4 augments neutrophil infiltration, and leukotrienes C4 and D4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5-lipoxygenase pathway in the course of glomerular injury is associated with a significant amelioration of the deterioration of renal hemodynamic and structural parameters. 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also generated in the course of glomerular injury. These eicosanoids have actions that contrast with those of leukotrienes. 15-S-HETE antagonizes leukotriene-induced neutrophil chemotaxis and lipoxin A4 antagonizes the effects of leukotrienes C4 and D4 on the glomerular microcirculation. The contrasting effects of 5- and 15-lipoxygenase products may represent endogenous pro- and anti-inflammatory influences that could ultimately regulate the extent and severity of glomerular inflammation. The recent availability of safe and effective 5-lipoxygenase inhibitors will be helpful to test the effect of blocking leukotriene production on the course of human glomerulonephritis and other disease states.