Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5‐HT receptor antagonists in a mouse model of allergic asthma

Abstract

1 Since both histamine and 5-hydroxytryptamine (5-HT) can be released by murine mast cells, we investigated the possible role of these autacoids on airway hyperresponsiveness (AHR), eosinophil in®ltration and serum-IgE levels in a murine model of allergic asthma. 2 Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml 71 ) or saline aerosols on 8 consecutive days. Starting one day before the challenge, animals were injected i.p. twice a day with a 5-HT-type 1 (5-HT 1 ) or type 2 (5-HT 2 ) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg 71 and ketanserin, 12 mg kg 71 , respectively) or a histamine-type 1 (H 1 ) or type 2 (H 2 ) receptor antagonist (mepyramine, 12 or 20 mg kg 71 and cimetidine, 10 or 25 mg kg 71 , respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an a-adrenoceptor antagonist (phentolamine, 5 mg kg 71 ). 3 In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was signi®cantly (9 fold increase, P50.01) increased when compared to vehicletreated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a signi®cant increase in both eosinophil numbers in bronchoalveolar lavage (BAL)¯uid (0+0, vehicle/ saline and 15.0+5.9610 4 cells vehicle/ovalbumin, P50.05) and ovalbumin-speci®c IgE levels in serum (157+69 and 617+171 units ml 71, respectively, P50.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all dierent treatments. 4 Treatment with ketanserin or cimetidine resulted in a partial but signi®cant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P50.05) and reduced eosinophil in®ltration after ovalbumin challenge by 60% and 58%, respectively. The combination of cimetidine and ketanserin almost completely abolished AHR whereas eosinophilia was decreased by 49%. No eects of these antagonists were observed on IL-16 levels in BAL¯uid or on serum antigen-speci®c IgE levels. Treatment with either the H 1 -receptor, the 5-HT 1 -receptor or the a-adrenoceptor antagonist, did not decrease the observed ovalbumin-induced airway responsiveness or eosinophilia in vehicle-treated animals. Higher doses of either methiotepine (2.0 mg kg 71 ) or mepyramine (20 mg kg 71 ) did decrease ovalbumin-induced eosinophil in®ltration (by 67%, P50.05 and 73%, respectively), whereas no eects of these antagonists were observed on ovalbumin-speci®c IgE levels in serum. 5 From these data it can be concluded that both histamine and 5-HT play a role in antigen-induced AHR and eosinophilia in the mouse.

Expression of P-Selectin at Low Site Density Promotes Selective Attachment of Eosinophils Over Neutrophils

“…An increased binding avidity of Eos for P-selectin was implicated as the reason up to 10-fold more Eos than PMNs selectively accumulated on airway endothelium (nasal polyps) in vitro (12). This was consistent with the finding in a murine asthma model that Ag-induced eosinophilia was blocked by preventing associated production of histamine, a selective inducer of endothelial cell P-selectin (13). Recent studies in P-selectin gene knockout mice have also supported P-selectin as an important element in Eos recruitment (14 -16).…”

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

“…Furthermore, antagonizing the NK 1 receptor has no influence on the increased activation status of alveolar macrophages after ovalbumin challenge in sensitized guinea pigs, suggesting no effect of the NK 1 receptor on the activation of macrophages in ovalbumin-sensitized and ovalbumin-exposed animals. 11 We did not observe any induced hyperresponsiveness in our model, although others did report allergen-induced hyperresponsiveness in mice, 21,22 guinea pigs, 23,24 and rats. 25 Therefore, no conclusions about the role of the NK 1 receptor in allergen-induced hyperresponsiveness could be made.…”

Induction and Inhibition of the Th2 Phenotype Spread: Implications for Childhood Asthma

“…Data shown are the mean Ϯ SEM of four mice from one of two independent experiments that yielded similar results. 22); 2) cromolyn, a mast cell stabilizer (23); and 3) various histamine receptor antagonists, including histamine type 1 or 2 receptor antagonists (mepyramine and cimetidine, respectively), and serotonin type 2 antagonist (katancerin) (24). None of these treatments altered the response to RW challenge (second challenge; data not shown).…”

“…injected 30 min before the each challenge of the first challenge period (23). Cimetidine (20 mg/kg), katancerin (20 mg/ kg), or mepyramine (20 mg/kg) was given twice daily every day throughout the first challenge period (24). For the passive transfer model, OVAhyperimmune serum, which was obtained from mice immunized with 20 g of OVA/500 g of alum four times, was transferred to the naive BALB/c mice.…”