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 infiltration and serum-IgE levels in a murine model of allergic asthma.

2. Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml⁻¹) 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-HT₁) or type 2 (5-HT₂) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg⁻¹ and ketanserin, 12 mg kg⁻¹, respectively) or a histamine-type 1 (H₁) or type 2 (H₂) receptor antagonist (mepyramine, 12 or 20 mg kg⁻¹ and cimetidine, 10 or 25 mg kg⁻¹, respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an α-adrenoceptor antagonist (phentolamine, 5 mg kg⁻¹).

3. In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was significantly (9 fold increase, P<0.01) increased when compared to vehicle-treated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a significant increase in both eosinophil numbers in bronchoalveolar lavage (BAL) fluid (0±0, vehicle/saline and 15.0±5.9×10⁴ cells vehicle/ovalbumin, P<0.05) and ovalbumin-specific IgE levels in serum (157±69 and 617±171 units ml⁻¹, respectively, P<0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all different treatments.

4. Treatment with ketanserin or cimetidine resulted in a partial but significant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P<0.05) and reduced eosinophil infiltration 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 effects of these antagonists were observed on IL-16 levels in BAL fluid or on serum antigen-specific IgE levels. Treatment with either the H₁-receptor, the 5-HT₁-receptor or the α-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⁻¹) or mepyramine (20 mg kg⁻¹) did decrease ovalbumin-induced eosinophil infiltration (by 67%, P<0.05 and 73%, respectively), whereas no effects of these antagonists were observed on ovalbumin-specific 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.

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