Effects of rolipram on responses to acute and chronic antigen exposure in monkeys.
The following study was performed to test the hypothesis that treatment with rolipram, a specific inhibitor of phosphodiesterase (PDE) IV, should inhibit many pulmonary responses to acute and chronic antigen challenge in atopic monkeys by elevating intracellular cAMP and subsequently inhibiting leukocyte function. Monkeys received subcutaneous injections of either vehicle (2% DMSO) or 10 mg/kg of rolipram 1 h before exposure to Ascaris suum antigen (Ag). Acute responses to Ag, including bronchoconstriction, pulmonary leukocyte infiltration, and cytokine production, were monitored before and 4 h after single Ag aerosol administration. To monitor the effects of rolipram on chronic Ag exposure, a 10-d, multiple-Ag protocol, previously demonstrated to induce airway hyperresponsiveness (AHR) to methacholine (MCh), was performed. Ag exposure increased respiratory system resistance (Rrs) 221.7 +/- 31.88% (n = 5). This increase in Rrs was not significantly altered by rolipram. Rolipram significantly (p < 0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5). Ag-induced increases in BAL IL-8 and TNF were significantly reduced by rolipram, but IL-1 beta and IL-6 increases were unaffected (n = 9). Ag-induced increases in BAL eosinophils and neutrophils were significantly reduced by rolipram (n = 9). In the multiple-Ag protocol (n = 7), rolipram significantly reduced both the number of BAL eosinophils (p < 0.02) and the development of AHR (p < 0.002). Despite its inability to inhibit acute Ag-induced bronchoconstriction, rolipram was protective against acute and chronic inflammatory responses to Ag and prevented the development of AHR, suggesting that selective PDE-IV inhibition is a relevant target for asthma therapy.
Turner
C R
CR
Department of Immunology and Infectious Diseases, Pfizer Central Research, Groton, CT 06340.
Andresen
C J
CJ
Smith
W B
WB
Watson
J W
JW
D000818:Animals; D000941:Antigens / Q000276:immunology*; D000947:Antigens, Helminth / Q000276:immunology; D017165:Ascaris suum / Q000276:immunology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D006969:Hypersensitivity, Immediate / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007958:Leukocyte Count; D008252:Macaca fascicularis; D008297:Male; D016210:Methacholine Chloride; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram
D000941:Antigens; D000947:Antigens, Helminth; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D016210:Methacholine Chloride; D020889:Rolipram; D004121:Dimethyl Sulfoxide