Differential effects of the PAF receptor antagonist UK‐74,505 on neutrophil and eosinophil accumulation in guinea‐pig skin

Abstract

1 The effect of the dihydropyridine, platelet activating factor (PAF) receptor antagonist, UK-74,505, on leucocyte accumulation and oedema formation in guinea-pig skin was investigated. The inflammatory reactions studied were elicited by exogenous mediators, a passive cutaneous anaphylactic (PCA) reaction and zymosan particles. 2 Leucocyte accumulation and oedema formation were measured as the local accumulation of i.v. administered "'In-labelled neutrophils or eosinophils together with '25I-labelled albumin. UK-74,505 was either administered i.v. or used to pretreat the radiolabelled leucocytes in vitro prior to their last wash and injection into recipient animals.3 In vitro, UK-74,505 inhibited PAF-induced elevations in cytoplasmic levels of Ca2+ ([Ca2+],) in fura-2-loaded guinea-pig neutrophils and eosinophils with IC50 values of 10-9 M and 7 x 10-9 M respectively. Neutrophils and eosinophils pretreated with 10-7 M and 10-6 M UK-74,505 respectively, and maintained at 37°C, were unresponsive to PAF for the 4 h period investigated. 4 In vivo, using 2 h test periods, i.v. UK-74,505 (0.5 and 2.5 mg kg-') inhibited the accumulation of "'In-neutrophils, "'In-eosinophils and oedema formation induced by intradermal PAF, but had no effect on responses elicited by leukotriene B4 (LTB4) and zymosan-activated plasma (ZAP, used as a source of C5a des Arg). UK-74,505 (2.5 mg kg-') was also without an effect on responses induced by a PCA reaction but significantly suppressed the "'In-eosinophil accumulation following the intradermal administration of zymosan particles. The "'In-neutrophil accumulation induced by zymosan particles was not, however, affected by UK-74,505. 5 In a second series of in vivo experiments, "'In-leucocytes were pretreated in vitro with UK-74,505 prior to their last wash and injection into recipient animals. Radiolabelled neutrophils, and eosinophils were pretreated with 10-7 M and 10-6 M UK-74,505 respectively, concentrations previously shown to block the leucocyte responses to PAF in vitro for up to 4 h. The in vitro pretreatment of the cells with the PAF antagonist, whilst not affecting the responses to intradermally-injected PAF, suppressed the "'In-eosinophil accumulation response induced by zymosan particles. 6 The results of this study indicate that PAF is not involved in neutrophil accumulation, eosinophil accumulation and oedema formation induced by LTB4, ZAP and a PCA reaction. Endogenous PAF does, however, appear to have a role in zymosan-induced eosinophil accumulation but not neutrophil accumulation, suggesting the existence of different inflammatory pathways in the induction of neutrophil and eosinophil accumulation in vivo. Furthermore, while leucocyte accumulation induced by exogenous PAF does not appear to involve leucocyte PAF receptors, the mechanism by which endogenous PAF mediates the zymosan-induced eosinophil accumulation appears dependent on the expression of PAF receptors on eosinophils.

Actions of PAF receptor antagonists in horses with the allergic skin disease sweet itch

“…In contrast, intravenous administration of two different PAF receptor antagonists did not inhibit oedema induced by antigen in a guinea pig passive cutaneous anaphylaxis (PCA) model of type 1 hypersensitivity [14,15]. Furthermore, leucocyte accumulation was not inhibited in these animals [15]. The effect of PAF receptor antagonists on antigen-induced inflammatory cell accumulation in the skin of human patients with allergic disease has not been reported.…”

“…In the guinea pig intravenous administration of the PAF receptor antagonists, WEB 2086 and UK-74,505, blocked oedema induced by intradermal injection of PAF [14,15]. Moreover, UK-74,505 inhibited the limited oedema response produced by intradermal administration of zymosan particles [15].…”

“…Moreover, oral administration of a PAF receptor antagonist inhibited oedema produced by injection of antigen into the skin of atopic volunteers [13]. In contrast, intravenous administration of two different PAF receptor antagonists did not inhibit oedema induced by antigen in a guinea pig passive cutaneous anaphylaxis (PCA) model of type 1 hypersensitivity [14,15]. Furthermore, leucocyte accumulation was not inhibited in these animals [15].…”

Substance P‐induced inflammatory responses in guinea‐pig skin: The effect of specific NK1 receptor antagonists and the role of endogenous mediators

“…Preparation of "'In-labelled guinea-pig neutrophils and eosinophils Guinea-pig peritoneal neutrophils and eosinophils were purified and radiolabelled with "'In chelated to 2-mercaptopyridine-N-oxide as previously described (Faccioli et al, 1991;Sanz et al, 1994). Briefly, to elicit neutrophils, ex-breeder guinea-pigs were injected i.p.…”

“…Cell populations were used only when the purity of the eosinophil preparation was above 95% and the purity of the neutrophil preparation was above 99%. The cells were then incubated with "'In (100 iCi in 10 ttl) (Faccioli et al, 1991;Sanz et al, 1994).…”