COMPARATIVE-EVALUATION OF ARACHIDONIC-ACID (AA)-INDUCED AND TETRADECANOYLPHORBOL ACETATE (TPA)-INDUCED DERMAL INFLAMMATION

The effects of topical application of arachidonic acid (AA) or phorbol ester, tetradecanoylphorbol 13-acetate (TPA), on edema response, vasc ular permeability, MPO, NAG, and generation of eicosanoids were studie d in two murine models of cutaneous inflammation. AA produced a short- lived edema response with a rapid onset that was associated with marke d increases in levels of prostaglandins (PGE2, 6-keto-PGF1alpha, PGF2a lpha), thromboxane B2 (TxB2) and leukotriene B4 (LTB4), With smaller i ncreases in levels of LTC4. TPA produced a longer-lasting edema that w as associated with marked influx of neutrophils and predominant format ion of LTB4 along with significant changes in levels of TxB2. Circulat ing T lymphocytes have no apparent role in the acute inflammatory resp onses induced by either agent. Arachidonic acid-induced vascular perme ability preceded the edema response and neutrophil influx, whereas TPA -induced vascular permeability paralleled the edema response and influ x of neutrophils. Mast cells appear to be important in the complete ex pression of inflammatory response, i.e., edema, cellular influx, and v ascular permeability induced by either AA or TPA, as these responses w ere blunted in mast cell-deficient mice. Inhibitors of CO or 5-LO atte nuated inflammatory responses in both models. The LTB4 receptor antago nist, SC-41930, inhibited the inflammatory response to TPA but had lit tle effect on that initiated by AA. This suggests that LTB4 is an impo rtant mediator in the phorbol ester-induced inflammatory response, whe reas peptidoleukotrienes and prostaglandins regulate vascular permeabi lity responses in the arachidonate model.