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In atopic subjects, intradermal injection of platelet-activating factor (PAF), 40 and 400 ng, resulted in an immediate edema reaction markedly blocked by cetirizine, 10 mg twice a day. PAF challenge also induced a significant eosinophil accumulation evidenced by a skin window technique at 2, 4, 8 and 24 h. This inflammatory phenomenon was significantly inhibited by cetirizine. In patients with chronic urticaria, PAF, 100 μg intradermally, induced immediate and late cutaneous reactions (LCR) also blocked by cetirizine, 10 mg twice a day. These LCR were accompanied by an infiltration of the deep dermis by degranulated eosinophils. The pathophysiological mechanism of the PAF-induced skin reactions is discussed as well as the mechanism of action of cetirizine. Correspondence to: Dr. L. Juhlin, Department of Dermatology, University Hospital, S–75185 Uppsala (Sweden) The increased vascular permeability induced by intradermal injection of platelet-activating factor (PAF) has been described by several investigators in experimental animals as well as in humans [1–4]. According to these authors, the PAF-induced flare is easily blocked by previous administration of Hi antihista-mines while the wheal appears rather poorly Hi-dependent. This is in accordance with the fact that PAF does not act as a histamine releaser in isolated human skin mast cells in vitro [5]. Nevertheless, we recently performed two clinical pharmacological studies in skin of atopies and patients with chronic urticaria challenged with PAF (40 and 400 ng in the atopies and 100 μg in the urticaria patients), and we showed that pretreatment with cetirizine, 10 mg twice a day (a dose which completely abolishes a skin wheal induced by a prick histamine at 500 mg/ml), not only inhibited the development of the flare but also markedly inhibited the wheal formation (50% decrease) [6,7]. Moreover, PAF, 100 μg intradermally, induced the development of a typical endematous and erythema-tous late cutaneous reaction (LCR) in urticaria patients, a phenomenon that was inhibited by 80% by cetirizine pretreatment. Taking into account all these above-mentioned data together with the facts that PAF was shown to induce a nonimmunological release of leukotrienes [8] and that a PAF-induced skin reaction may be blocked by PAF antagonists [9–11], it becomes possible to propose the following hypothetical mechanism in order to explain the immediate PAF-induced skin reaction in humans. The flare might result from a classical axon reflex phenomenon mediated by PAF receptors on the nerves’ endings of the C fibers. As far as the wheal is concerned, we might assume that it partly depends on a direct effect of PAF on the skin vessels on the one hand, and on the other hand that it is partly due to a local appearance of other vasoactive mediators such as leukotrienes and histamine. The origin of these mediators remains to be determined. A local interference D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 0/ 20 17 8 :2 7: 57 P M between these vasoactive mediators (PAF, leukotrienes, histamine) and neuromediators releasedlocally cannot be excluded.The PAF-induced LCR observed in urticaria patients may be partly secondary to the localincrease in vessel permeability allowing plasma factors to infiltrate the perivascular spaces andto cause a local delayed inflammation. Indeed, it must be emphasized that the intradermalinjection of the urticaria patient’s own serum is followed by an LCR peaking at 6 h. If histaminerepresents a significant part of the mediators responsible for the observed increase in vessel300Rihoux/Fadel/Juhlin permeability, this may explain the marked inhibiting effect of cetirizine on this LCR.Nevertheless, the serum-induced LCR is rather small in comparison with the LCR induced byPAF, and this is why a second possibility for explaining the PAF-induced LCR is the markedinfiltration of the deep dermis by de-granulated eosinophils [12]. Actually, the PAF-inducedLCR in urticaria patients might be due to a conjunction of vessel hyperpermeability and eosino-philic infiltration.Similarly, the inhibiting effect of cetirizine on this LCR might also be linked to the well-documented inhibition by cetirizine of the eosinophils’ migration [13–17].ReferencesHumphrey DM, McManus LM, Satouchi K, Hanahan DJ, Pinckard N: Vasoactive properties ofacetyl glyceryl ether phos-phorylcholine and analogues. Lab Invest 1982;46:422.Archer CB, Page CP, Paul W, Morley J, MacDonald DM: Inflammatory characteristics ofplatelet activating factor (PAF-acether) in human skin. Br J Dermatol 1984; 110:45–50.Archer CB, MacDonald DM, Morley J, Page CP, Paul W, San-jar S: Effects of serum albumin,indomethacin and histamine H,-antagonists on Paf-acether-induced inflammatory responses inthe skin of experimental animals and man. Br J Pharmacol 1985;85:109–113.Chung KF, Minette P, McCusker M, Barnes PJ: Ketotifen inhibits the cutaneous but not theairway responses to platelet-activating factor in man. J Allergy Clin Immunol 1988;81:1192–1198.Thomas G, Church MK: Platelet activating factor does not release histamine from humandispersed cutaneous mast cells. Clin Exp Allergy 1990;20:377–382.Fadel R, David B, Herpin-Richard N, Borgnon A, Rassemont R, Rihoux J-P: In vivo effects ofcetirizine on cutaneous reactivity and eosinophil migration induced by platelet-activating factor(PAF-acether) in man. J Allergy Clin Immunol, in press.Juhlin L, Rihoux J-P: Effect of cetirizine on cutaneous reactions to PAF, kallikrein and serum inpatients with chronic urticaria. Acta Derm Venereol (Stockh) 1990;70:151–153. Voelkel NF, Worthen S, Reeves JT, Henson PM, Murphy RC: Nonimmunological production ofleukotrienes induced by platelet-activating factor. Science 1982;218:15.Guinot P, Braquet P, Duchier J, Cournot A: Inhibition of PAF-acether-induced wheal and flarereaction in man by a specific PAF antagonist. Prostaglandins 1986;32:160–163. Roberts NM, Page CP, Chung KF, Barnes PJ: Effect of a PAF antagonist, BN52063, on antigen-induced, acute, and late-onset cutaneous responses in atopic subjects. J Allergy Clin Immunol1988;82:236–241. Downloadedby: 54.70.40.11-11/20/20178:27:57PM Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ: Effect of a ginkgolide mixture(BN52063) in antagonising skin and platelet responses to platelet-activating factor in man.Lancet 1987;i:248–251.Archer CB, Page CP, Morley J, MacDonald DM: Accumulation of inflammatory cells inresponse to intracutaneous platelet activating factor (PAF-acether) in man. Br J Dermatol1985;112:285–290.Fadel R, Herpin-Richard N, Rihoux JP, Henocq E: Inhibitory effect of cetirizine 2 HC1 oneosinophil migration in vivo. Clin Allergy 1987;17:373–379.Michel L, De Vos C, Rihoux J-P, Burtin C, Benveniste J, Du-bertret L: Inhibitory effect of oralcetirizine on in vivo antigen-induced histamine and PAF-acether release and eosinophilrecruitment in human skin. J Allergy Clin Immunol 1988;82: 101–109.Charlesworth EN, Kagey-Sobodka A, Norman PS, Lichten-stein LM: Effect of cetirizine on mastcell-mediator release and cellular traffic during the cutaneous late-phase reaction. J Allergy ClinImmunol 1989;83:905–912.Leprevost C, Capron M, De Vos C, Tomassini M: Inhibition of eosinophil chemotaxis by a newantiallergic compound (cetirizine). Int Arch Allergy Appl Immunol 1988;87:9–13.Henocq E, Rihoux J-P: Does reversed-type anaphylaxis in healthy subjects mimic a real allergicreaction? Clin Exp Allergy 1990;20:269–272. Downloadedby: 54.70.40.11-11/20/20178:27:57PM