Fifteen-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 an 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 microM 15-S-HETE) but, the same concentration did not inhibit chemotaxis to n-formyl-1-methionyl-1-phenylalanine (FMP). 12-S-HETE (30 microM) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Fischer
D B
DB
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Christman
J W
JW
Badr
K F
KF
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains
D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid