The effect of 5-lipoxygenase inhibition on Ascaris antigen (Ag)-induced responses in atopic monkeys
Related Experiment Videos
C R Turner1, W B Smith, C J Andresen
1Department of Immunology and Infectious Diseases, Pfizer Central Research, Groton, CT 06340, USA.
Abstract:
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.
Insights
Two 5-lipoxygenase (5LO) inhibitors, ZD2138 and Zileuton, effectively reduced acute inflammatory responses to Ascaris suum (Ag) in monkeys. However, ZD2138 did not prevent chronic inflammation or airway hyperresponsiveness after repeated Ag exposure.
Area of Science:
- Pharmacology
- Immunology
- Respiratory Medicine
Background:
- Asthma and allergic airway diseases involve inflammatory pathways.
- 5-lipoxygenase (5LO) is a key enzyme in leukotriene synthesis, contributing to inflammation.
- Leukotrienes, such as LTB4 and LTE4, play significant roles in allergic responses.
Purpose of the Study:
- To investigate the efficacy of 5LO inhibitors ZD2138 and Zileuton in mitigating acute and chronic allergic airway inflammation.
- To assess the impact of these inhibitors on leukotriene production and inflammatory cell infiltration in a primate model.
Main Methods:
- Atopic Macaca fascicularis monkeys were treated with vehicle, ZD2138, or Zileuton.
- Ex vivo leukotriene B4 (LTB4) production was measured in whole blood stimulated with Ca2+ ionophore.
- Bronchoalveolar lavage (BAL) fluid was analyzed for leukotriene E4 (LTE4) levels, neutrophils, IL-6, and IL-8 following aerosolized Ascaris suum (Ag) challenge.
- A separate study evaluated ZD2138's effect on chronic Ag-induced inflammation and airway hyperresponsiveness (AHR).
Main Results:
- Both ZD2138 and Zileuton significantly inhibited ex vivo LTB4 production.
- ZD2138 (10 mg/kg) markedly reduced BAL LTE4 levels, neutrophils, and IL-6 post-Ag challenge.
- Zileuton also inhibited these acute inflammatory markers and reduced IL-8 levels.
- ZD2138 treatment failed to prevent pulmonary inflammation or AHR in the chronic exposure model.
Conclusions:
- 5LO inhibition effectively reduces acute inflammatory responses and leukotriene production in a primate model of allergic airway inflammation.
- While beneficial for acute inflammation, ZD2138 did not demonstrate efficacy in preventing chronic inflammation or airway hyperresponsiveness.
- These findings highlight the role of 5LO in acute allergic responses but suggest limitations in targeting chronic inflammatory processes with these inhibitors alone.