RT Journal Article
SR Electronic
T1 Characterisation of a steroid-insensitive severe asthma model
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P1781
VO 44
IS Suppl 58
A1 Puneeta Nath
A1 Alan Young
A1 Vince Russell
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P1781.abstract
AB Approximately 10% of asthmatics can be classified as having severe asthma. Inhaled steroids are often ineffective in these patients and they are often characterised as having neutrophilic lung inflammation. Here we report on the development of a pre-clinical severe asthma model characterised by neutrophilic inflammation and steroid insensitivity.Female BALB/c mice were sensitised subcutaneously on day 0 with 100μg of house dust mite (HDM) in Complete Freund's Adjuvant (CFA). On day 14, mice were exposed to saline or 100µg HDM by the intranasal (i.n.) route. Prior to HDM-challenge, animals were treated with 0.1, 0.3 or 1mg/kg, i.n., Budesonide. Twenty-four hours following challenge, animals were sacrificed and inflammation quantified in the bronchoalveolar lavage fluid.Sensitised mice challenged with HDM had a significant increase in pulmonary inflammation compared to saline-challenged controls. The inflammation consisted of neutrophils (0.8±0.2 x106 vs 0.1±0.01 x106) and eosinophils (0.4±0.2 x106 vs 0.01±0.01 x 106), elevated levels of Th-1 cytokines, e.g., IL-2 (29.0±13.3 vs 9.6±01.1 pg/ml) and Th-2 cytokines, e.g., IL-4 (2352±1241 vs 4.5±3.3 pg/ml). Histopathology revealed increased clara cell hyperplasia and mucus cell metaplasia. Budesonide failed to show activity against any of the readouts examined.The HDM/CFA model exhibits both neutrophilic and eosinophilic inflammation, along with structural changes in the airways, which is steroid insensitive at doses shown to inhibit in an HDM/alum model. Taken together, these data suggest that the HDM/CFA model may prove to be a useful pre-clinical model for the assessment of novel compounds for the treatment of severe asthma.