title: Fifteen-S-hydroxyeicosatetraenoic acid (15-S-HETE) specifically antagonizes the chemotactic action and glomerular synthesis of leukotriene B4 in the rat.
abstract: 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)
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: D B
authors.initials: DB
authors.lastname: Fischer
authors.forename: J W
authors.initials: JW
authors.lastname: Christman
authors.forename: K F
authors.initials: KF
authors.lastname: Badr
mesh_terms: 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
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid