15-S-HYDROXYEICOSATETRAENOIC ACID (15-S-HETE) SPECIFICALLY ANTAGONIZES THE CHEMOTACTIC ACTION AND GLOMERULAR SYNTHESIS OF LEUKOTRIENE-B4 IN THE RAT

In models of experimental glomerulonephritis, there is temporal concordance between the shift in the glomerular cellular infiltrate from neutrophils (PMN) to macrophages/monocytes and the suppression of glomerular leukotriene B4 (LTB4) generation. Since macrophages are a rich source of 15-lipoxygenase (15-LO) products, we investigated whether the principal product of arachidonate 15-lipoxygenation, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), was capable of antagonizing the proinflammatory actions of LTB4 in the rat. PMN exhibited chemotaxis to LTB4 in a dose dependent manner with in LC50 of 10(-8) M. When rat neutrophils were pre-treated with 15-S-HETE, chemotaxis to LTB4 was inhibited in a dose dependent manner (maximal at 30-mu-M 15-S-HETE) but, the same concentration did not inhibit chemotaxis to n-formyl-l-methionyl-1-phenylalanine (FMP). 12-S-HETE (30-mu-M) did not inhibit chemotaxis to LTB4. Glomeruli from rats injected with nephrotoxic serum three hours earlier generated increased levels of LTB4; prior exposure of such glomeruli to 15-S-HETE totally normalized LTB4 production. The glomerular production of 15-S-HETE and LTB4 was also determined 3 hours, 72 hours and 2 weeks after administration of nephrotoxic serum. Whereas there was an early, short-lived, burst of LTB4 followed by a return to baseline levels, the production of 15-S-HETE increased steadily over the two week period and was present in amounts fivefold greater than LTB4. Thus, these studies assign a role for locally generated 15-LO derivatives in arresting LTB4-promoted PMN infiltration and suppressing LTB4 synthesis. Coupled with our previous demonstration of counterregulatory interactions between lipoxins and cysteinyl leukotrienes, the current studies provide further support for a generalized anti-inflammatory role for 15-LO products through specific antagonism and/or inhibition of leukotriene synthesis and biologic activities.