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Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen‐induced airway responses in neonatally immunised rabbits
Author(s) -
Gozzard N.,
ElHashim A.,
Herd C.M.,
Blake S.M.,
Holbrook M.,
Hughes B.,
Higgs G.A.,
Page C.P.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15524.x
Subject(s) - bronchoconstriction , budesonide , bronchoalveolar lavage , histamine , antigen , medicine , pharmacology , immunology , airway resistance , corticosteroid , anesthesia , lung , endocrinology , asthma
1 The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systemically, were evaluated in a model of antigen‐induced airway inflammation in the rabbit. 2 Adult litter‐matched NZW rabbits (2.4‐3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 μg, inhaled over 2 days) or CDP840 (total dose 7 mg kg −1 , i.p. over 3 days), before antigen challenge. For each drug‐treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3 Basal lung function in terms of total lung resistance ( R L ; cmH 2 O 1 −1 s −1 ) and dynamic compliance ( C dyn ; ml cmH 2 O −1 ) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4 The R L component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in C dyn due to antigen. Treatment with CDP840 significantly reduced antigen‐induced acute bronchoconstriction in terms of both R L and C dyn . 5 Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced R L PC 50 (2.4‐4.5 fold) and C dyn PC 35 (2.1–3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen‐induced increase in responsiveness to inhaled histamine. 6 Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen‐induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen‐induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7 Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen‐induced increase in total lung resistance ( R L ); however, both drugs prevented the antigen‐induced reduction in dynamic compliance ( C dyn ). CDP840 and budesonide also prevented antigen‐induced AHR and eosinophilia in the immunised rabbit.