title: Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen.
abstract: We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl derivative of D-serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a rapamycin derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen. Bronchoconstrictor responses to adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg(-1) were reduced dose-dependently by budesonide, IMM125, and MLD987, given i.t. 25 and 1 h prior to allergen challenge. In contrast, SAR943 had no effect on responses to adenosine. Responses to methacholine and 5-HT were minimally affected by these agents. Bronchoconstrictor responses to bradykinin were dose-dependently reduced by budesonide, but unaffected following IMM125, MLD987 or SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg(-1), induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activities and protein concentration measured 24 h post challenge. Budesonide (1 mg kg(-1) given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of inflammation; IMM125 and MLD987, at a dose of 1 mg kg(-1) had no significant effect whereas SAR943 reduced lymphocyte numbers. Thus, budesonide, IMM125 and MLD987 block the hyperresponsiveness to adenosine induced by allergen challenge in sensitised rats. In the case of budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.
authors.affiliation: Novartis Institute for Biomedical Research, WSJ.386.508, 4002 Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tigani
authors.forename: Jason P
authors.initials: JP
authors.lastname: Hannon
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schaeublin
authors.forename: Lazzaro
authors.initials: L
authors.lastname: Mazzoni
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D016085:Bronchoconstrictor Agents; D003524:Cyclosporins; C082770:IMM 125; D016210:Methacholine Chloride; D019819:Budesonide; D010047:Ovalbumin; C476498:SAR943; D000241:Adenosine; D001920:Bradykinin; D020123:Sirolimus