Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model.
Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in allergic airway inflammation, that can be significantly attenuated by therapeutic intervention with phosphodiesterase 4 inhibition and corticosteroid treatment. Female BALB/c mice were administered intranasally with HDM (Dermatophagoides pteronyssinus) extract daily for five weeks, and therapeutic intervention with anti-inflammatory treatment (dexamethasone 1 mg/kg subcutaneous once daily, prednisolone 10mg/kg orally twice daily, fluticasone 3, 10 and 30 microg intranasally twice daily, roflumilast 10 mg/kg orally twice daily and intranasally 10 and 30 microg twice daily) was initiated after three weeks of exposure. Chronic HDM extract exposure resulted in significant airway inflammation, demonstrated by bronchoalveolar lavage cell infiltration and lung tissue inflammatory gene expression by TaqMan low density array. Chronic steroid treatment significantly inhibited these parameters. In addition, roflumilast caused a significant reduction in airway inflammatory cell infiltration. We have demonstrated that chronic HDM-induced allergic inflammation can be significantly ameliorated by steroid treatment, and that phosphodiesterase 4 inhibition modulates inflammatory cell infiltration. Therefore, the murine HDM model may be a useful tool for evaluating new targets for the treatment of asthma.
Ulrich
Kristina
K
Drug Safety Research and Development, Pfizer Global Research and Development, Sandwich, Sandwich, UK. Kristina.ulrich@pfizer.com
Hincks
Jennifer S
JS
Walsh
Roddy
R
Wetterstrand
E M Caroline
EM
Fidock
Mark D
MD
Sreckovic
Sasha
S
Lamb
David J
DJ
Douglas
Garry J
GJ
Yeadon
Michael
M
Perros-Huguet
Christelle
C
Evans
Steven M
SM
D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology
D000631:Aminopyridines; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D003521:Cyclopropanes; D005938:Glucocorticoids; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D003907:Dexamethasone; D011239:Prednisolone; D000068298:Fluticasone