title: Allergen challenge alters lymphocyte phosphodiesterase activity in horses with heaves.
abstract: Heaves is an allergic airway disease in horses characterised by reversible airway obstruction, bronchial hyperresponsiveness and airway inflammation associated with a Th(2) response. Cyclic nucleotide-dependent signalling pathways can regulate lymphocyte function. In this study, we examined lymphocyte PDE activity comparing horses with heaves to healthy control animals. Total PDE activity and the effects of isoenzyme selective inhibitors were measured before, 5 and 24 h after the start of a 7 h allergen challenge. Allergen challenge had no effect on either total cAMP PDE activity or its inhibition by the PDE4 selective inhibitor, rolipram, and the non-selective PDE inhibitor, theophylline. In contrast, the PDE3 selective inhibitor, quazinone, caused significantly greater inhibition of cAMP PDE activity before challenge in the heaves susceptible group. Additionally, total cGMP PDE activity was significantly lower 24 h after the start of challenge in the heaves affected group (11+/-2 and 21+/-3 pmol/min/mg for heaves and control animals, respectively) and the PDE5 selective inhibitor, zaprinast, caused significantly less inhibition in the heaves group at this time point. The functional significance of these findings was explored by examining the effect of PDE3, PDE4 and PDE5 selective inhibitors on mitogen-induced mononuclear cell proliferation before and 24 h after the start of allergen challenge. Proliferation decreased after challenge in the heaves group (stimulation index=328+/-110 and 200+/-72 before and after challenge, respectively) whilst remaining constant in the control group (stimulation index=161+/-13 and 183+/-45 before and after challenge, respectively). However, all three PDE inhibitors caused a similar amount of inhibition at each time point and the effect of a combination of a PDE3 and a PDE5 inhibitor was simply additive in both groups. These results suggest differences in the control of lymphocyte PDE activity in horses with heaves.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawkshead Campus, North Mymms, Hatfield, Herts AL9 7TA, UK. karen.rickards@kcl.ac.uk
authors.forename: K J
authors.initials: KJ
authors.lastname: Rickards
authors.forename: C P
authors.initials: CP
authors.lastname: Page
authors.forename: F M
authors.initials: FM
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000276:immunology / Q000662:veterinary*; D001985:Bronchial Provocation Tests / Q000662:veterinary; D016084:Bronchoconstriction; D006734:Horse Diseases / Q000201:enzymology* / Q000276:immunology; D006736:Horses; D008214:Lymphocytes / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases