Parainfluenza 3 viral exacerbation of ovalbumin-induced pulmonary inflammation in guinea-pigs is resistant to fluticasone

William Ford, Amy Herbert, Emma Kidd, Kenneth Broadley. Cardiff University, Cardiff, United Kingdom.

Viral exacerbations of asthma appear to be associated with corticosteroid resistance in humans (Schuh et al., 2000). Our aim was to determine if viral exacerbation using parainfluenza 3 (PIV-3) virus, of ovalbumin (OA)-induced pulmonary inflammation in sensitised guinea-pigs, is resistant to treatment with fluticasone.

Male Dunkin-Hartley guinea-pigs (300-350 g) were sensitised with 100 μg OA + 100 mg Al2OH3 in 1ml normal saline (i.p.) on days 2 and 6. Specific airway conductance (sGaw) was measured using whole body plethysmography. PIV-3 (106 infectious units) or media without virus was nasally instilled on days 11 and 12. Animals were treated with nebulised fluticasone propionate (∼1.5 mg per day) or its vehicle (DMSO:ethanol:saline, 30:30:40%) from days 10-15. All animals were challenged for 1 h with nebulised OA (10 μg/ml) on day 15 and repeated measurements of sGaw made over a 24 h period. Total and differential cell counts were made from bronchoalveolar lavage obtained at the end of the protocol. Airway hyperreactivity was determined by exposing guinea-pigs to a single 20 sec, subthreshold dose (1 mM) of histamine 1 day before sensitisation and again 24 h after OA challenge. Measurements of sGaw after OA challenge are plotted as % change from baseline and total bronchoconstriction is reported as mean area under the curve ± SEM, n=5-6 animals.

Compared to vehicle control in the absence of PIV-3, fluticasone reduced the overall bronchoconstriction in response to OA challenge (679±162 vs 233±79 %.h, respectively, P<0.05), limited total inflammatory cell influx (57±6 ×105 vs 3±1 ×105, respectively, P<0.05) and reduced airway hyperreactivity to histamine. In guinea-pigs inoculated with PIV-3, compared to vehicle control, fluticasone did not affect overall bronchoconstriction in response to OA challenge (695±227 vs 538±105 %.h, respectively) or inflammatory cell influx (11±2 ×106 vs 6±2 ×106, respectively). However, airway hyperreactivity to 1 mM histamine was significantly inhibited in fluticasone-treated animals compared to vehicle controls. PIV-3 exacerbation of OA-induced pulmonary inflammation in guinea-pigs is resistant to treatment with fluticasone. This data indicates that our viral-exacerbation model may be a useful model to study the aetiology and treatment of steroid resistance.

Schuh et al (2000) New Eng. J. Med., 343, 689-694.