A comparison of antiasthma drugs between acute and chronic ovalbumin- challenged guinea-pig models of asthma Rhys L. Evans a , Anthony T. Nials b , Richard G. Knowles b , Emma J. Kidd a , William R. Ford a , Kenneth J. Broadley a, * a Division of Pharmacology, Cardiff School of Pharmacy & Pharmaceutical Technology, Cardiff University, Redwood Building, King Edward VII Avenue, Cathays Park, Cardiff CF13XF, United Kingdom b Respiratory Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG12NY, United Kingdom article info Article history: Received 16 May 2012 Received in revised form 8 August 2012 Accepted 10 August 2012 Keywords: Chronic guinea-pig asthma models Remodelling Airways hyperresponsiveness Early and late asthmatic responses Fluticasone propionate Roflumilast GW274150 abstract Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been devel- oped in mice but few studies use guinea-pigs which may be more relevant to humans. We tested the hypothesis that a chronic rather than acute pulmonary inflammation model would best predict clinical outcome for asthma treatments. Guinea-pigs sensitized with ovalbumin (OVA) received single (acute) or nine OVA inhalation challenges at 48 h intervals (chronic). Airways function was recorded as specific airways conductance (sG aw ) in conscious animals for 12 h after OVA challenge. AHR to inhaled histamine, inflammatory cell influx and lung histology were determined 24 h after the single or 9th OVA exposure. The inhaled corticosteroid, fluticasone propionate (FP), the phosphodiesterase 4 inhibitor, roflumilast, and the inducible nitric oxide synthase (iNOS) inhibitor, GW274150, orally, were administered 24 and 0.5 h before and 6 h after the single or final chronic OVA exposure. Both models displayed early (EAR) and late (LAR) asthmatic responses to OVA challenge, as falls in sG aw , AHR, as increased histamine-induced bronchoconstriction, and inflammatory cell influx. Tissue remodelling, seen as increased collagen and goblet cell hyperplasia, occurred after multiple OVA challenge. Treatment with FP and roflumilast inhibited the LAR, cell influx and AHR in both models, and the remodelling in the chronic model. GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodies- terase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Asthma is a chronic inflammatory airways disorder, yet most pre-clinical models concentrate on acute inflammation following allergen exposure [1]. There are a number of potentially important differences between acute and chronic inflammation. The acute inflammatory response is limited to the proximal airways and is not associated with tissue remodelling [2]. The cytokine profile of the lungs also varies with the number of allergen challenges [3]. These differences might explain why drug testing using current pre- clinical animal models does not always translate into the clinic, resulting in substantial losses in time and money. Several studies in mice have used multiple exposures to allergen to induce chronic inflammation in which structural changes to the airways have been observed which are inhibited by corticosteroids and phosphodiesterase inhibitors [4e6]. However, there have been very few studies performed in guinea-pigs using chronic exposures Non-standard abbreviations: AHR, airway hyperresponsiveness; BAL, bron- choalveolar lavage; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guano- sine monophosphate; EAR, early asthmatic response; FP, fluticasone propionate; HDM, house dust mite; iNOS, inducible nitric oxide synthase; LAR, late asthmatic response; NO, nitric oxide; OVA, ovalbumin; PDE4, phosphodiesterase type 4. * Corresponding author. Division of Pharmacology, Cardiff School of Pharmacy & Pharmaceutical Sciences, Cardiff University, PO Box 13, Cathay’s Park, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom. Tel.: þ44 (0)29 20875832; fax: þ44 (0)29 20874149. E-mail address: BroadleyKJ@Cardiff.ac.uk (K.J. Broadley). Contents lists available at SciVerse ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt 1094-5539/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.08.004 Pulmonary Pharmacology & Therapeutics xxx (2012) 1e12 Please cite this article in press as: Evans RL, et al., A comparison of antiasthma drugs between acute and chronic ovalbumin-challenged guinea- pig modelsof asthma, Pulmonary Pharmacology & Therapeutics (2012), http://dx.doi.org/10.1016/j.pupt.2012.08.004