Leukotriene D4 receptor antagonism reduces airway hyperresponsiveness in monkeys.
Airway hyperresponsiveness (AHR) and pulmonary inflammation are observations that are consistently associated with asthma and also occur in a well-characterized monkey model of asthma. The following study was performed to determine whether treatment with an LTD4 receptor antagonist, ICI 198,615, could attenuate antigen-induced pulmonary inflammation and AHR in monkeys using the following protocol. On day 0, the PC200 (the concentration of methacholine (MCh) that doubled respiratory system resistance, Rrs) was determined in 6 male, atopic, cynomolgus monkeys, previously characterized in historical control trials (Control #1) as airway hyperresponsive. Bronchoalveolar lavage (BAL) was then performed to determine total and differential leukocyte counts. On days 3, 5 and 7, each monkey received 10 mg/kg ICI 198,615 (im) 30 min prior to Ascaris suum (Ag) aerosol exposures which doubled Rrs. On day 10, the post-Ag PC200 to MCh was determined and BAL was repeated. Five weeks after this trial was complete, a bracketing control trial (Control #2) was performed in which the monkeys were administered vehicle prior to each Ag exposure. In comparison to the response in both control trials, treatment with the LTD4 antagonist significantly (P < 0.05) inhibited the development of AHR and also significantly reduced (P < 0.05) peripheral blood lymphocyte counts after Ag challenge. Treatment with ICI 198,615 reduced the Ag-induced increase in BAL eosinophils, but statistical significance was obtained only when treated animals were compared to Control #1, not Control #2.(ABSTRACT TRUNCATED AT 250 WORDS)
Turner
C R
CR
Department of Immunology and Infectious Diseases, Pfizer Central Research, Groton, Connecticut 06340.
Smith
W B
WB
Andresen
C J
CJ
Swindell
A C
AC
Watson
J W
JW
D000818:Animals; D000941:Antigens; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D007191:Indazoles / Q000097:blood / Q000627:therapeutic use*; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D020024:Leukotriene Antagonists; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors
D000941:Antigens; D007191:Indazoles; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D013189:SRS-A; C054217:ICI 198615; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor