Canine in vivo tracheal chemotaxis of eosinophils to antigen in sensitized dogs: inhibition by a steroid, a systemic lazaroid U-78517F, and several topical H1 antihistamines.
Inflammation of the airways contributes to the multicomponent disease known as asthma. The primary cells that infiltrate the airway in response to antigen exposure are neutrophils and eosinophils. Eosinophils have been implicated in much of the histopathology of the airway following infiltration and degranulation. We used topical antigen exposure in the trachea of sensitized beagle dogs to study the kinetics of eosinophil infiltration with a modified double balloon endotracheal tube technique. After establishment of the eosinophilia, we used inhibitors with known actions to implicate certain mediators in the cellular response. Beagle dogs were sensitized to ascaria ova by feeding them orally by gavage. After 6 wk, challenge with 2.0 micrograms/ml ascaris antigen protein via the tracheal chamber resulted in a rapid (maximal in 4 h) and repeatable influx (p less than 0.05 versus vehicle) of eosinophils that was faster and larger than that of exogenously added LTB4 or PAF exposure. After 4 to 6 separate (every 2 wk) antigen challenges in which the response varied by (SEM +/- 13 to 50%), the individual dogs were rechallenged in the presence of various inhibitors administered either topically in the perfusate or systemically. The inhibitors that were effective in blocking the eosinophil influx by a statistically significant amount were: (1) the lazaroid U-78517F orally 0.5 to 30 mg/kg-18 h (2) Medrol acetate 5 mg/kg intramuscularly-18 h, (3) H1-antihistamines topically (10(-6) M) Astemizole, Cetirizine, and Mepyramine, also orally 30 mg/kg, and Azelastine. Inhibitors falling to inhibit influx topically were a LTB4 receptor antagonist (U-75302) and U-80271 (Merck L-652731), a PAF antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypersensitivity Diseases Research and Medical Chemistry Research, Upjohn Company, Kalamazoo, Michigan 49001.
H G
HG
Johnson
M L
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McNee
R A
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Nugent
D000704:Analysis of Variance; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage; D001200:Ascaris / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000453:epidemiology / Q000209:etiology; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007114:Immunization / Q000379:methods; D008297:Male; D008775:Methylprednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077555:Methylprednisolone Acetate; D010879:Piperazines / Q000494:pharmacology*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D000947:Antigens, Helminth; D002839:Chromans; D006634:Histamine H1 Antagonists; D010879:Piperazines; C066382:U 78517F; D000077555:Methylprednisolone Acetate; D008775:Methylprednisolone