Effects of theophylline and rolipram on antigen-induced airway responses in neonatally immunized rabbits.
1. The effects of the xanthine, theophylline, a non-selective phosphodiesterase (PDE) inhibitor, and the phosphodiesterase type 4 (PDE 4) inhibitor, rolipram, were evaluated in a model of antigen-induced airway responses in the allergic rabbit. 2. Adult litter-matched NZW rabbits (2.5-3.9 kg), immunized within 24 h of birth with Alternaria tenuis antigen, were pretreated twice daily for 3 days with theophylline (3 mg kg-1, i.p) or rolipram (1 mg kg-1, i.p) prior to antigen challenge (Alternaria tenuis). For each drug-treated group, a parallel group of rabbits were pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine and bronchoalveolar lavage (BAL) was performed 24 h before and after antigen-challenge. 3. Basal lung function in terms of resistance (RL, cmH2O 1(-1)s-1) and dynamic compliance (Cdyn, ml cmH2O-1) were unaltered by pretreatment with theophylline or rolipram compared to their respective vehicles 24 h prior to or post antigen challenge. 4. The acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with theophylline or rolipram. 5. Airway hyperresponsiveness to inhaled histamine was indicated by reduced RL PC50 (2.4-3.5 fold) and Cdyn PC35 (2.5-2.6 fold) values 24 h after antigen challenge. Treatment with rolipram, but not theophylline, prevented the increase in responsiveness to inhaled histamine 24 h after antigen challenge. 6. Total cells per ml of BAL fluid increased 24 h after antigen challenge due to the recruitment of neutrophils and eosinophils. Antigen-induced increases in pulmonary neutrophils were unaffected; however, eosinophils were reduced 57.5% in theophylline and 82% in rolipram-treated rabbits. 7. Inhalation of Alternaria tenuis aerosol elicits an acute bronchoconstriction, followed 24 h later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment in the immunized rabbit. With the dosing regimes used, both rolipram and theophylline inhibited eosinophil recruitment, whilst only rolipram prevented the development of airway hyperresponsiveness. Neither agent inhibited the acute bronchoconstriction due to inhaled antigen.
Gozzard
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N
Department of Pharmacology, Celltech Therapeutics Ltd., Slough, Berkshire.
Herd
C M
CM
Blake
S M
SM
Holbrook
M
M
Hughes
B
B
Higgs
G A
GA
Page
C P
CP
D000403:Airway Resistance; D000528:Alternaria / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000946:Antigens, Fungal; D001249:Asthma / Q000276:immunology; D001986:Bronchial Spasm / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D005260:Female; D006632:Histamine; D007958:Leukocyte Count; D008170:Lung Compliance; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D012130:Respiratory Hypersensitivity / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D020889:Rolipram; D013806:Theophylline / Q000494:pharmacology* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D000946:Antigens, Fungal; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D006632:Histamine; D013806:Theophylline; D020889:Rolipram