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Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5‐HT receptor antagonists in a mouse model of allergic asthma
Author(s) -
De Bie J J.,
Henricks P A J.,
Cruikshank W W.,
Hofman G,
Jonker E H.,
Nijkamp F P.,
Van Oosterhout A J M.
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701901
Subject(s) - histamine , eosinophilia , asthma , airway hyperresponsiveness , medicine , bronchial hyperresponsiveness , immunology , 5 ht receptor , receptor , pharmacology , serotonin , respiratory disease , lung
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. 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‐HT 1 ) or type 2 (5‐HT 2 ) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg −1 and ketanserin, 12 mg kg −1 , respectively) or a histamine‐type 1 (H 1 ) or type 2 (H 2 ) 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 ). 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±5.9×10 4 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. 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 H 1 ‐receptor, the 5‐HT 1 ‐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. 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.