Interference of cetirizine with the late eosinophil accumulation induced by either PAF or compound 48/80.

1. The effect of topical or systemic treatment with the histamine H1-receptor antagonist, cetirizine, on the rat pleural eosinophil accumulation induced by PAF or compound 48/80 was investigated. The number of pleural resident eosinophils increased 6 h after the intrathoracic (i.t.) injection of PAF (1 microgram/cavity), peaked within 24 h and persisted significantly augmented for at least 96 h. Compound 48/80 (25 micrograms/cavity) also produced a long lasting pleural eosinophilia but this was first noted only 24 h after stimulation. 2. Intraperitoneal pretreatment with cetirizine inhibited eosinophilia induced by either PAF (ED50 = 19 mg kg-1) or compound 48/80 (ED50 = 14 mg kg-1) whereas meclizine, another histamine H1-receptor antagonist, was inactive. 3. Administered locally, cetirizine (5 and 15 micrograms/cavity) also dose-dependently inhibited both PAF- and compound 48/80-induced eosinophilia, providing evidence that its inhibitory effect is not due to any action upon circulating eosinophils. Consistent with this result, incubation of isolated peritoneal eosinophils with cetirizine failed to modify in vitro eosinophil migration caused by PAF. 4. Since the late eosinophilia induced by PAF may depend on the synthesis of a transferable protein mediator, cetirizine was administered to donor or recipient rats in order to determine whether it interferes with the generation or with the expression of this protein. We showed that only the treatment of recipient rats abolished the transfer of the eosinophilotactic activity, indicating that cetirizine does not modify the generation but inhibits the expression of this activity. 5. Our findings indicate that cetirizine is able to inhibit eosinophil accumulation by acting locally. The mechanism is neither related to its recognized ability to antagonize histamine H,-receptors nor to a direct action upon circulating eosinophils.

Homologous tachyphylaxis to bradykinin and its interference with allergic pleurisy in actively sensitized rats.

After recovery from a first intraplantar or intrathoracic stimulation with bradykinin, repeated daily provocation with this peptide resulted in a progressive loss of its ability to cause paw or pleural oedema, reaching 0-20% of the control within seven and four consecutive provocations, respectively. The phenomenon was shown to be time reversible, since the unresponsiveness ceased when stimulations were discontinued, and localized, since paw oedema evoked by the peptide was not modified after desensitization of either the contralateral paw or the pleural cavity. Furthermore desensitization to bradykinin did not influence the pleurisy elicited by either histamine (200 micrograms/cavity), 5-hydroxytryptamine (5-HT) (100 microgram/cavity) or platelet-activating factor (PAF) (1 microgram/cavity), suggesting that the desensitization was selective. In contrast, when actively sensitized animals were submitted to bradykinin-induced tachyphylaxis, pleural exudation and leukocyte influx induced by antigen were drastically reduced, strongly implying bradykinin in this process. We demonstrated that repeated daily stimulation with bradykinin cause selective, local and reversible auto-refractoriness, which may be useful as a tool in attempting to evaluate the role of this peptide in inflammation.

Suppression by cetirizine of pleurisy triggered by antigen in actively sensitized rats.

The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged with an intrathoracic injection of ovalbumin (12 micrograms/cavity), which caused drastic mast cell degranulation, followed by pleural oedema and leucocyte influx. Cetirizine and meclizine (2.5-30 mg/kg i.p.), 1 h before challenge, inhibited the exudatory response evoked by antigen, under conditions where neutrophil and eosinophil accumulation was affected only by the former. When administered intrathoracically 22 h after allergen, i.e. using a curative approach, cetirizine (15 micrograms/cavity) drastically reduced the pleural eosinophilia noted 24 h post-challenge, indicating that this drug can reverse an already established eosinophilia. Cetirizine (15 mg/kg i.p.) also restored, to about 39% (P < 0.001), the number of uninjured mast cells recovered from the pleural cavity following allergen stimulation. In normal rats, cetirizine (5-15 micrograms/cavity) completely inhibited the pleural exudation elicited by histamine and only partially the exudation caused by 5-hydroxytryptamine or bradykinin, but was quite inactive against platelet-activating factor. We conclude that the pleural exudation triggered by allergen, vasoactive amines or bradykinin is clearly sensitive to cetirizine. In addition, the ability of the drug to interfere with pleural neutrophil or eosinophil mobilization and mast cell degranulation seems not to be associated with its ability to block the histamine H1 receptor.

Systemic and local dexamethasone treatments prevent allergic eosinophilia in rats via distinct mechanisms.

We have studied the effect of local and systemic treatment with dexamethasone for prevention of the pleural eosinophilia triggered by allergen in actively sensitised Wistar rats. Parallel changes in blood and marrow eosinophil numbers were assessed for comparison. The intrapleural (i.pl.) injection of ovalbumin into ovalbumin-sensitised animals led to a long-lasting pleural fluid eosinophilia which peaked from 24 to 72 h post-challenge. At these time points, there was a significant 2- to 3-fold increase in the blood eosinophil numbers, whereas the bone marrow number of mature eosinophils remained unaltered. Systemic treatment with dexamethasone (0.05-0.5 mg/kg, i.p.) abolished the pleural and blood eosinophilia observed 24 and 48 h post-challenge, also causing a significant reduction in marrow eosinophil numbers. Despite being unable to alter blood and bone marrow eosinophil numbers, the local i.pl. administration of dexamethasone (2.5-10 microg/cavity) inhibited dose dependently the allergen-induced pleural eosinophil influx at 24 h but not at 48 h post-challenge. This treatment also shortened the time course of eosinophil accumulation in the pleural space from the 48 h time point on. We conclude that the effect of systemic but not of local treatment with dexamethasone on allergen-induced eosinophil recruitment is well correlated with the inhibition of eosinophil production in bone marrow. In contrast, low amounts of dexamethasone injected into the pleural space seem to affect locally eosinophil recruitment and survival.

Eosinophil accumulation in the rat pleural cavity after mast cell stimulation with compound 48/80 involves protein synthesis and is selectively suppressed by dexamethasone.

Alterations in the local mast cell population and the eosinophil accumulation in the rat pleural cavity were studied using pleurisy induced by compound 48/80, a standard mast-cell-degranulating agent. Twenty-four hours after the intrathoracic injection of compound 48/80 (1-50 micrograms/cavity), a dose-dependent eosinophil enrichment of the exudate was noted, concomitantly with a drastic reduction in the total number of undamaged mast cells recovered from the pleural washing. At 24 h, neutrophil counts were not modified, and the number of mononuclear cells was increased, but only at the highest dose of compound 48/80. The temporal analysis showed that mast cell degranulation, exudation and neutrophil infiltration were maximal at the interval of 1-6 h after compound 48/80 (25 micrograms/cavity), whereas eosinophil accumulation peaked within 24 h, persisting elevated at least until 96 h. Since compound 48/80 was itself unable to induce eosinophil migration in vitro, attempts were made to investigate the potential involvement of recognized eosinophil chemo-attractants, such as histamine, leukotriene B4 (LTB4) and platelet-activating factor (PAF-acether). The intraperitoneal pretreatment with either cyproheptadine (2 mg/kg), meclizine (40 mg/kg), BW755C (25 mg/kg) or with the PAF-acether receptor antagonist WEB 2086 (20 mg/kg) had no effect on the eosinophil recruitment induced by compound 48/80 (25 micrograms/cavity). However, the treatment with the corticosteroid dexamethasone or the local inhibition of protein biosynthesis with cycloheximide (0.04-200 nmol/cavity) blocked the eosinophil pleural accumulation, but not the mast cell degranulation induced by compound 48/80. Our findings indicate that the pleural eosinophil accumulation induced by compound 48/80 is sensitive to dexamethasone, requires local protein biosynthesis and is independent of histamine, LTB4 and PAF-acether.

Bradykinin induces eosinophil accumulation in the rat pleural cavity.

Intrathoracic injections of bradykinin (1-100 micrograms/cavity) induced a dose-dependent increase in the number of eosinophils recovered from the rat pleural cavity 24 h later. Eosinophilia by bradykinin was preceded by a marked pleural neutrophil influx within 6 h and was absent only 72 h following stimulation. Bradykinin (10(-9)-10(-5) M) failed to induce in vitro eosinophil chemotaxis, indicating that its in vivo effect must be mediated by an intermediate messenger. BW 755C (25 mg/kg) and the more selective lipoxygenase inhibitor BW A4C (20 micrograms/cavity) suppressed the pleural eosinophilia induced by bradykinin (50 micrograms/cavity), whereas the platelet-activating factor (PAF)-acether antagonist BN 52021 was inactive. We conclude that bradykinin is able to attract eosinophil in vivo by a mechanism independent of PAF-acether and sensitive to the blockage of the lipoxygenase pathway.