Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig.
Male Dunkin Hartley guinea pigs, actively sensitized to ovalbumin (OA) and pretreated with mepyramine (1 mg/kg i.p.), were challenged with OA as an aerosol. Histological analysis of the lung for eosinophils (EOs) showed significant accumulations in the submucosa of the airways (8 h: 1.477.3 +/- 43 EOs/mm2 airway, n = 3, p less than 0.01), after antigen challenge compared to saline control (478.6 +/- 104 EOs/mm2 airway, n = 4). Pretreatment with both mepyramine and cimetidine (10 mg/kg i.p.) did not affect this response. Aerosolization of OA to unsensitized guinea pigs resulted in no significant accumulation of EOs (360.2 +/- 49 EOs/mm2 airway, n = 4) when compared with the saline-challenged sensitized control group. Pretreatment with the leukotriene (LT)D4 receptor antagonist MK-571 (1 mg/kg p.o.) significantly inhibited the OA-induced EO migration (95 +/- 5% inhibition, n = 5, p less than 0.01) compared to vehicle in the presence of mepyramine and cimetidine, while indomethacin (3 mg/kg p.o., n = 4) had no effect. Aerosolization of synthetic LTC4 (0.3-30 micrograms/ml) resulted in a dose-dependent migration of EOs into the submucosal layer over 8 h, reaching significance at the 10-micrograms/ml dose, with comparable results obtained with LTD4. Pretreatment of animals with MK-571 (1 mg/kg p.o.) before LTC4 and LTD4 aerosol results in inhibition of the response in both cases, suggesting that this effect may be mediated through the LTD4 receptor. We conclude that peptide LTs produce eosinophilia in the airways of the guinea pig.
Foster
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Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Chan
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D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D002465:Cell Movement; D002927:Cimetidine / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology*; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011422:Propionates / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000187:drug effects; D018077:Receptors, Leukotriene
D015289:Leukotrienes; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; C059141:verlukast; D002927:Cimetidine; D010047:Ovalbumin; D011738:Pyrilamine; D007213:Indomethacin