Effect of a 5 - lipoxygenase inhibitor , ZM 230487 , on cutaneous allergic inflammation in the guinea - pig ' Mauro

1 Leukotrienes have potent biological effects in vitro and in vivo and are found in tissue and in biological fluids in various pathological conditions including allergic diseases. Leukotriene B4 (LTB4) is a potent stimulus for eosinophil accumulation and activation and there is much interest in determining its importance in mediating the accumulation of eosinophils at sites of allergic inflammation in vivo. In this study, we investigated the effects of a potent 5-lipoxygenase inhibitor, ZM 230487, on the accumulation of eosinophils and on local oedema formation in cutaneous inflammation in the guinea-pig. 2 The i.d. injection of increasing concentrations of arachidonic acid (AA) led to a dose-dependent accumulation of "'In-eosinophils but oedema formation was only significant at the top dose of AA tested (3 x 10mol per site). Co-injection of ZM 230487 with AA inhibited "'In-eosinophil accumulation up to 99% but the small oedema response to AA was only partially inhibited. AA-induced oedema formation was only effectively inhibited when a combination of a PAF antagonist, an antihistamine and ZM 230487 was used. 3 Local administration of the cyclo-oxygenase inhibitor, ibuprofen, partially inhibited AA-induced oedema formation suggesting that vasodilator prostaglandins may be released following i.d. injection of AA. AA-induced "'1In-eosinophil accumulation was also partially inhibited by ibuprofen. 4 PAF-induced "'In-eosinophil accumulation was partially suppressed by local administration of ZM 230487. In contrast, LTB4-induced "'In-eosinophil accumulation was enhanced by ZM 230487. These data suggest that locally-released leukotrienes may modulate mediator-induced eosinophil accumulation. ZM 230487 had no effect on PAF-or LTB4-induced oedema formation.