Enhancement of acute allergic inflammation by indomethacin is reversed by prostaglandin E2: apparent correlation with in vivo modulation of mediator release.

Abstract

Intravital microscopy and determination of in vivo histamine release revealed that the cyclooxygenase inhibitor indomethacin reduced antigen-induced vasodilation while enhancing plasma extravasation, leukocyte accumulation, and histamine release in cheek pouches of immunized hamsters. Topical application of prostaglandin E2 (PGE2, 30 nM) totally reversed the indomethacin-induced potentiation of the inflammatory reaction to antigen challenge and suppressed both the histamine release and plasma leakage also in the absence of indomethacin. On the other hand, PGE2, which per se caused vasodilation, markedly potentiated the postcapillary leakage of plasma induced by histamine or leukotriene C4, as well as the leukocyte activation and subsequent plasma extravasation evoked by leukotriene B4. Taken together, the data indicate that PGE2 reduced the antigen response by suppression of mediator release from the numerous mast cells present in the cheek pouch. Moreover, the PGE2-sensitive potentiation by indomethacin of the antigen response suggests that endogenous vasodilating prostaglandins (possibly PGE2) predominantly were antiinflammatory.The potent vasodilator prostaglandin E2 (PGE2) is released at sites of inflammation, causes a wheal and flare reaction when injected into skin, and enhances the effects of pain-and edema-producing stimuli (cf. ref. 1). Moreover, nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the fatty acid cyclooxygenase, which catalyzes the initial steps in the biosynthesis of PGE2 from arachidonic acid (cf. ref. 1). Hence, PGE2 is considered to be an inflammatory mediator. Nevertheless, PGE2 and related compounds also exhibit antiinflammatory activities (2-8), and NSAIDs sometimes augment inflammation (9, 10). These conflicting observations complicate understanding of the functional role of PGE2 in inflammation.In the present study, intravital microscopy of the hamster cheek pouch was used to characterize the influence of PGE2 and the prototype of NSAIDs, indomethacin, on microcirculatory dynamics during acute mast cell-dependent inflammation evoked by antigen challenge. Supported also by in vivo measurements of antigen-induced histamine release from the cheek pouch and analysis of the microvascular interactions between exogenous inflammatory mediators and PGE2, we conclude that endogenous cyclooxygenase products predominantly inhibit acute allergic inflammation via local suppression of inflammatory mediator release.MATERIALS AND METHODS Drugs and Chemicals. Leukotrienes B4 and C4 (LTB4, LTC4) were provided by J. Rokach (Merck Frosst Labs, Pointe Claire, PQ) and PGE2 by J. Pike (Upjohn). Arachidonic acid was from Nu Chek Prep. Stock solutions of LTB4, PGE2, and arachidonic acid were stored at -20°C in ethanol, and LTC4 was stored similarly in ethanol/water, 1:1. Concentrations and purity of the icosanoids were checked before use by appropriate methods (UV spectrometry, reverse-phase HPLC, and thin-layer chromatography). Acetylcholine chloride, fluorescein isothiocyanate-conjugated dextr...

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