Mary F. Fitzgerald

The anaphylactic release of platelet-activating factor from perfused guinea-pig lungs

1 The release of platelet‐activating factor (Paf‐acether) and of its inactive precursor/metabolite lysoplatelet activating factor (lyso‐Paf) from control and sensitized guinea‐pig isolated lungs challenged with antigen was investigated. 2 Control guinea‐pig lungs perfused either through the pulmonary circulation or through the airways and challenged with antigen did not release Paf‐acether. 3 Sensitized guinea‐pig isolated lungs perfused through the pulmonary circulation and challenged with antigen released lyso‐Paf but not Paf‐acether. 4 Sensitized guinea‐pig isolated lungs perfused through the airways and challenged with antigen released three times more lyso‐Paf and also Paf‐acether. 5 These results support a possible role for Paf‐acether in respiratory anaphylaxis in the guinea‐pig.

Inhibition of antigen-induced contraction of guinea-pig airways by a leukotriene synthesis inhibitor, BAY x1005

BAY x1005 ((R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid), an inhibitor of leukotriene synthesis, was evaluated, both in vitro and in vivo, for inhibition of antigen-induced airway contraction in the sensitised guinea-pig. Antigen (ovalbumin 0.001-10 micrograms/ml) challenge of tracheae in the presence of pyrilamine and indomethacin induced contractile responses which were inhibited by BAY x1005 with an IC50 value of 0.36 (0.2-0.8) microM. Using the same test system BAY x1005 (1 microM), ICI D2138 (0.3 microM) or AA 861 (1 microM) had similar inhibitory activities, whereas MK 886, MK 591, and Zileuton (A64077) all tested at 1 microM and REV 5901 (10 microM) had no significant effect. Using tracheae from non-sensitised (control) guinea-pigs the calcium ionophore A23187 (1 microM) induced a maximal contraction which was significantly inhibited by BAY x1005 at 1 microM, whereas MK 886 was only active at 3 microM. BAY x1005 tested at 10 microM and 3 microM had no effect against leukotriene D4- or KCl-induced contractions of guinea-pig tracheae respectively. In the anaesthetised ovalbumin sensitised guinea-pig BAY x1005 caused a dose-related inhibition of ovalbumin-induced bronchoconstriction, with approximate ID50 values of 0.85 mg/kg i.v. and 6.3 mg/kg p.o. In the same model MK 886, MK 591, AA 861 and ICI D2138 each given at 10 mg/kg p.o. had no significant inhibitory activity against antigen challenge. Six hours after administration BAY x1005 (10 mg/kg p.o.) was still effective against the antigen-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)

The release of lyso-PAF from guinea-pig lungs.

Lyso-PAF was detected after ionophore challenge in the effluent of lungs of guinea-pigs exposed to oxygen and perfused through the pulmonary circulation as well as of control lungs perfused through the airways. Lyso-PAF is probably the inactive metabolite of PAF-acether which could not, itself, be detected in the lung effluents.

The effect of glucocorticoids on lyso-PAF formationin vitro andin vivo

Introduction During the last few years increasing experimental evidence has accumulated which indicates that PlateletActivating Factor (PAF-acether, AGEPC) is a potential mediator of inflammation and anaphylaxis [1]. This polar lipid is synthetized by a two stage process in which the ether phosphatide precursor is catalytically transformed to lyso-PAF by phospholipase A2 (PLA2) and then acetylated by a specific acetyltransferase [2]. Glucocorticoids suppress PLA2 activity by inducing the synthesis/release of an inhibitor protein (lipocortin) [3,4]. Here we report the effect of glucocorticoids and lipocortin on the formation of PAFacether and lyso-PAF in vitro by rat peritoneal macrophages and guinea-pig sensitized lungs and in vivo in rat pleural inflammatory exudates.

Release of PAF-acether and eicosanoids from guinea-pig alveolar macrophages by FMLP: effect of cyclo-oxygenase and lipoxygenase inhibition

Adherent guinea-pig alveolar macrophages stimulated in vitro with FMLP (1 microM) for 5-60 min released PAF-acether, TXB2 and LTB4, with maximal levels being achieved after a 5 min incubation. The levels of eicosanoids were maintained during the 60 min incubation period, whereas the levels of PAF-acether decreased and were no longer detectable after 60 min incubation. Indomethacin (1 microM) completely suppressed the release of TXB2 stimulated by FMLP (1 microM for 5 min) whilst potentiating the release of LTB4. The selective 5-lipoxygenase inhibitor, BW A137C (1 microM), abolished the stimulated release of LTB4 without affecting the release of TXB2. BW755C (1-20 microM) caused a dose-related inhibition of TXB2 release but did not affect LTB4 release, while none of the drugs studied affected the release of PAF-acether. These results indicate that the FMLP-induced release of PAF-acether from guinea-pig alveolar macrophages is not susceptible to modulation by selective inhibition of lipoxygenase or cyclo-oxygenase and is therefore not secondary to the synthesis of LTB4 or TXB2.