Leukotriene Modulation and Inhibitor Impact on Guinea Pig Allergic Inflammation

Leukotrienes, known for their significant biological impact in both in vitro and in vivo conditions, are prevalent in various pathological states, including allergic diseases. This research explores the role of leukotriene B4 (LTB4) in eosinophil accumulation and its implications in allergic inflammation. The study's focus is on the impact of the 5-lipoxygenase inhibitor, ZM 230487, on eosinophil accumulation and edema in guinea-pig cutaneous inflammation.

In intradermal (i.d.) injections, arachidonic acid (AA) led to a dose-dependent eosinophil accumulation, with edema formation being significant only at the highest AA dose. The co-administration of ZM 230487 significantly reduced eosinophil accumulation, but only partially inhibited the edema caused by AA. Notably, effective inhibition of AA-induced edema required a combination of a PAF antagonist, an antihistamine, and ZM 230487.

The cyclooxygenase inhibitor, ibuprofen, was found to partially inhibit AA-induced edema, suggesting a role for vasodilator prostaglandins in the response to AA. Ibuprofen also showed a partial inhibitory effect on AA-induced eosinophil accumulation.

ZM 230487 partially suppressed platelet-activating factor (PAF)-induced eosinophil accumulation but interestingly enhanced leukotriene B4 (LTB4)-induced eosinophil accumulation, indicating a modulatory role of locally released leukotrienes on mediator-induced eosinophil accumulation. However, ZM 230487 did not affect edema formation induced by PAF or LTB4.

In passive cutaneous anaphylaxis (PCA) reactions, ZM 230487 significantly inhibited eosinophil accumulation without impacting edema formation. The PAF antagonist WEB 2086, alone or combined with ZM 230487, did not influence eosinophil accumulation or edema in the PCA reaction.

The study concludes that a 5-lipoxygenase product, likely LTB4, plays a crucial role in eosinophil accumulation in guinea-pig skin during PCA reactions, but not in local edema formation. These findings underscore LTB4's significant role in allergic inflammation and validate the guinea-pig PCA model as a suitable system for examining the effects of leukotriene synthesis or action inhibitors in vivo.