title: Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation.
abstract: The effects of topical application of arachidonic acid (AA) or phorbol ester, tetradecanoylphorbol 13-acetate (TPA), on edema response, vascular permeability, MPO, NAG, and generation of eicosanoids were studied in two murine models of cutaneous inflammation. AA produced a short-lived edema response with a rapid onset that was associated with marked increases in levels of prostaglandins (PGE2, 6-keto-PGF1 alpha, PGF2 alpha), thromboxane B2 (TxB2) and leukotriene B4 (LTB4), with smaller increases in levels of LTC4. TPA produced a longer-lasting edema that was associated with marked influx of neutrophils and predominant formation of LTB4 along with significant changes in levels of TxB2. Circulating T lymphocytes have no apparent role in the acute inflammatory responses induced by either agent. Arachidonic acid-induced vascular permeability preceded the edema response and neutrophil influx, whereas TPA-induced vascular permeability paralleled the edema response and influx of neutrophils. Mast cells appear to be important in the complete expression of inflammatory response, i.e., edema, cellular influx, and vascular permeability induced by either AA or TPA, as these responses were blunted in mast cell-deficient mice. Inhibitors of CO or 5-LO attenuated inflammatory responses in both models. The LTB4 receptor antagonist, SC-41930, inhibited the inflammatory response to TPA but had little effect on that initiated by AA. This suggests that LTB4 is an important mediator in the phorbol ester-induced inflammatory response, whereas peptidoleukotrienes and prostaglandins regulate vascular permeability responses in the arachidonate model.
authors.affiliation: Searle Research & Development, Monsanto Company, St. Louis, Missouri 63198.
authors.forename: T S
authors.initials: TS
authors.lastname: Rao
authors.forename: J L
authors.initials: JL
authors.lastname: Currie
authors.forename: A F
authors.initials: AF
authors.lastname: Shaffer
authors.forename: P C
authors.initials: PC
authors.lastname: Isakson
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity*; D002199:Capillary Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced; D015777:Eicosanoids / Q000096:biosynthesis; D005260:Female; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D009195:Peroxidase; D000118:Acetylglucosaminidase; D013755:Tetradecanoylphorbol Acetate