Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiological and immunological processes are not fully understood. Animal models have been used to elucidate asthma pathophysiology, and to identify and evaluate novel therapeutic targets. Several recent review articles (Epstein, 2004; Lloyd, 2007; Boyce and Austen, 2005; Zosky and Sly, 2007) have discussed the potential value of these models. Allergen challenge models reproduce many features of clinical asthma and have been widely used by investigators; however, the majority involve acute allergen challenge procedures. It is recognised that asthma is a chronic inflammatory disease resulting from continued or intermittent allergen exposure, usually via inhalation, and there has been a recent focus on developing chronic allergen exposure models, predominantly in mice. Here, we review the acute and chronic exposure mouse models, and consider their potential role and impact in the field of asthma research.

BackgroundAsthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β2 adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E2 (PGE2)-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro.MethodsUsing an extensive range of pharmacological tools, the relaxant potential of PGE2 and selective agonists for the EP1–4 receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated.ResultsIn agreement with previous studies, it was found that the EP2 receptor mediates PGE2-induced relaxation of guinea pig, murine and monkey trachea and that the EP4 receptor mediates PGE2-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP2 receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP4 receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP2 agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies.ConclusionIdentification of the receptor mediating PGE2-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP2 receptor agonists in clinical studies.

1 Salmeterol, a novel, long-acting /J-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of f-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2 Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F2. or electrical stimulation) and human bronchus (contracted by PGF2a) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3 Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by sahueterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the fl-adrenoceptor blocking drug, propranolol (O.1juM). In further studies, on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA2 of 9.0. The slope of the Schild plot was 1.02. 4 Another /i-adrenoceptor blocking drug, sotalol (10pM), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5 In the fJ,-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000-5000 fold less potent, and appeared to be partial agonists. At a concentration of 72#M, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 pM). 6 On the guinea-pig isolated gastric fundus strip, a putative /3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,3-adrenoceptor agonist, BRL 35135.7 In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h. 8 Salmeterol is therefore a potent and selective 12-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inha...

1 This study has explored the mechanism underlying the long duration of action of the R2-adrenoceptor agonist, salmeterol. 2 Salmeterol, salbutamol and isoprenaline caused a concentration-related inhibition of electricallyinduced contractile responses of the guinea-pig superfused trachea preparation. The effects of both isoprenaline and salbutamol were rapid in onset and rapidly reversed upon removal of the agonist. In contrast, the effects of salmeterol were slower in onset and could not be reversed by superfusion of the tissue with agonist-free Krebs solution even for periods of up to 10 h.3 The effects of salmeterol were, however, readily reversed by a number of P-adrenoceptor blocking drugs, as was the effect of a continuous infusion of isoprenaline. Upon removal of the antagonist, however, the effects of salmeterol and of the isoprenaline infusion were reasserted at a rate which was inversely related to the lipophilicity of a P-adrenoceptor blocking drugs. 4 Salmeterol inhibited the binding of [121I](_ )-iodopindolol (100 pM) to rat lung membranes (pIC5o 7.1), with isoprenaline (pICo 6.2) and salbutamol (pIC50 5.1) having lower potencies. The inhibition of binding by salmeterol was apparently non-competitive, whereas that produced by salbutamol and isoprenaline was competitive in nature. 5 Isoprenaline and salbutamol rapidly dissociated from their binding sites, whereas in marked contrast, the binding of salmeterol showed no dissociation for periods of up to 1 h. 6 These data are consistent with a mechanism in which salmeterol binds adjacent to the active site of the 2-adrenoceptor, such that the drug cannot be washed out of the tissue, yet can interact with and activate the receptor. This latter property is susceptible to antagonism by P-adrenoceptor blocking drugs but is reasserted when the antagonists are removed.

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