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 he modynamic and structural deterioration during experimental glomerulone phritis. Generation of these metabolites is largely by infiltrating le ukocytes, but can also occur by intrinsic glomerular cells via transce llular metabolism of intermediates. In several animal models of glomer ulonephritis and other renal pathologic states, leukotrienes have been shown to exert adverse effects in the glomerulus. Leukotriene B-4 aug ments neutrophil infiltration, and leukotrienes C-4 and D-4 mediate po tent vasoconstrictor effects on the glomerular microcirculation. Selec tive blockade of the 5-lipoxygenase pathway in the course of glomerula r injury is associated with a significant amelioration of the deterior ation of renal hemodynamic and structural parameters. 15-S-hydroxyeico satetraenoic acid (15-S-HETE), the immediate product of arachidonate 1 5-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also gener ated in the course of glomerular injury. These eicosanoids have action s that contrast with those of leukotrienes. 15-S-HETE antagonizes leuk otriene-induced neutrophil chemotaxis and lipoxin A(4) antagonizes the effects of leukotrienes C-4 and D-4 On the glomerular microcirculatio n. The contrasting effects of 5- and 15-lipoxygenase products may repr esent endogenous pro- and anti-inflammatory influences that could ulti mately regulate the extent and severity of glomerular inflammation. Th e 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.