The effect of 5-lipoxygenase inhibition on Ascaris antigen (Ag)-induced responses in atopic monkeys.
The effects of two 5-lipoxygenase (5LO) inhibitors, ZD2138 or Zileuton, on acute, inflammatory responses to aerosolized Ascaris suum (Ag) were determined in atopic Macaca fascicularis monkeys. Monkeys (n = 6 each group) were dosed with vehicle, 3 or 10 mg/kg ZD2138, or 30 mg/kg Zileuton (p.o.). Both ZD2138 or Zileuton significantly inhibited ex vivo LTB4 production in Ca2+ ionophore-stimulated whole blood from these same monkeys (n = 6 each group) by 45.5% (3 mg/kg ZD2138), 82.5% (10 mg/kg ZD2138) and 84.3% (30 mg/kg Zileuton). ZD2138 (10 mg/kg) reduced bronchoalveolar lavage (BAL) LTE4 levels (65.1% inhibition), BAL neutrophils (88.9% inhibition), and IL-6 (54.0% inhibition) 4h post Ag. Zileuton inhibited these responses and also reduced BAL levels of IL-8 (73.4% inhibition). A second study was performed to evaluate the effects of ZD2138 on chronic Ag-induced responses. Treatment with ZD2138 did not prevent pulmonary inflammation or the development of airway hyperresponsiveness (AHR). Based upon these results, 5LO inhibition significantly reduced ex vivo LTB4 and in vivo LTE4 production as well as several acute inflammatory responses to Ag in the lung. However, ZD2138 did not inhibit more chronic responses following multiple Ag exposure.
Turner
C R
CR
Department of Immunology and Infectious Diseases, Pfizer Central Research, Groton, CT 06340, USA.
Smith
W B
WB
Andresen
C J
CJ
Eggler
J F
JF
Watson
J W
JW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000947:Antigens, Helminth / Q000276:immunology*; D017165:Ascaris suum / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology*; D007958:Leukocyte Count; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D009504:Neutrophils; D011714:Pyrans / Q000008:administration & dosage / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000947:Antigens, Helminth; D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; C063449:zileuton; D006918:Hydroxyurea