Cutaneous inflammation: effects of hydroxy acids and eicosanoid pathway inhibitors on vascular permeability.
Four metabolic products of arachidonic acid lipoxygenation, 5-hydroxyeicosatetraenoate (5-HETE), 12-HETE, 15-HETE, 5(S),12(S)-DiHETE, were injected intradermally into depilated dorsae of albino guinea pigs. The presence of intravenously injected 125I-bovine serum albumin (10uCi/kg) in 13-mm punch biopsy specimens served as a marker for altered vascular response; histologic changes were evaluated at 6 and 24 h after the injection in 1-micron-thick sections. Thirty minutes after the injections of 15 nanomoles and 60 nanomoles of 5-HETE, the ratios of radioactivity in HETE-injected to that in buffer-injected sites were 1.35 +/- 0.06 (mean +/- SE) and 2.80 +/- 0.27, respectively. Corresponding effects of 15-HETE were 1.39 +/- 0.17 and 1.63 +/- 0.21, respectively. Values for 60 nanomoles of 12-HETE and 5,12-DiHETE were intermediate in comparison with the above eicosanoids. The most notable histologic changes were a neutrophilic infiltrate induced by 12-HETE at 6 and 24 h, and neutrophilic and eosinophilic infiltrates in response to 5,12-DiHETE injection at 6 and 24 h. Effects of topically applied eicosanoid pathway inhibitors were also evaluated, using intradermally injected sodium arachidonate (AA) as agonist. Three mixed cyclooxygenase/lipoxygenase inhibitors, BW755C, phenidone, and nordihydroguaiaretic acid, suppressed vascular response by 9%, 9%, and 6% for 150 nmol of AA, and by 9%, 13%, and 12% for 300 nmol of AA, respectively. The cyclooxygenase inhibitor, indomethacin, induced suppressions of 39% for 150 nmol AA and 22% for 300 nmol AA, respectively. These data demonstrate that metabolites of both cyclooxygenase and lipoxygenase eicosanoid pathways are involved in alteration in vascular response accompanying cutaneous inflammation.
Waldman
J S
JS
Dermatology Service, New York Veterans Administration Medical Center, New York.
Marcus
A J
AJ
Soter
N A
NA
Lim
H W
HW
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors; D002199:Capillary Permeability / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D003872:Dermatitis / Q000473:pathology / Q000503:physiopathology*; D004804:Eosinophils / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007271:Injections, Intradermal; D009504:Neutrophils / Q000473:pathology
D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D001091:Arachidonate Lipoxygenases