Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma.
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 alpha-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 x 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. 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 alpha-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.
Department of Pharmacology and Pathophysiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
J J
JJ
De Bie
P A
PA
Henricks
W W
WW
Cruikshank
G
G
Hofman
E H
EH
Jonker
F P
FP
Nijkamp
A J
AJ
Van Oosterhout
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004802:Eosinophilia / Q000097:blood / Q000473:pathology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013388:Succinimides / Q000737:chemistry / Q000378:metabolism
D016085:Bronchoconstrictor Agents; D006633:Histamine Antagonists; D012702:Serotonin Antagonists; D013388:Succinimides; D016210:Methacholine Chloride; D007073:Immunoglobulin E; C036068:N-amino-3-bromophenylsuccinimide; D010047:Ovalbumin