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 developed 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
phosphodiesterase 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.