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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 3, 2003; DOI: 10.1124/jpet.103.053819

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*Asthma
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*DEXAMETHASONE


Received for publication May 5, 2003.
Revised May 21, 2003.
Accepted for publication June 30, 2003.

Inhibition of Inflammation and Remodeling by Roflumilast and Dexamethasone in Murine Chronic Asthma

Rakesh K. Kumar 1*, Cristan Herbert 1, Paul S. Thomas 1, Lutz Wollin 2, Rolf Beume 2, Ming Yang 3, Dianne C. Webb 3, Paul S. Foster 3

1 The University of New South Wales 2 ALTANA Pharma AG 3 Australian National University

* Address correspondence to: E-mail: r.kumar{at}unsw.edu.au

Abstract

Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a non-selective inhibitor) and dexamethasone in ameliorating the lesions of chronic asthma in a mouse model. BALB/c mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 6 weeks. During weeks 5 and 6, groups of animals were treated with roflumilast or dexamethasone by daily gavage, or with pentoxifylline by daily intraperitoneal injection. Airway hyper-reactivity (AHR) was evaluated by whole body plethysmography and airway lesions by histomorphometry and immunohistochemistry. Compared to vehicle alone, treatment with roflumilast or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization and thickening of the airway epithelium. Dexamethasone also reduced goblet cell hyperplasia/metaplasia, subepithelial accumulation of transforming growth factor-{beta}1 and epithelial cytoplasmic immunoreactivity for nuclear factor-{kappa}B. Treatment with pentoxifylline inhibited only eosinophil recruitment and epithelial thickening. Roflumilast and dexamethasone slightly decreased AHR, whereas this was significantly reduced by pentoxifylline. Thus, in this model of chronic asthma, both roflumilast and dexamethasone were potent inhibitors of airway inflammation and remodeling. Roflumilast did not diminish accumulation of transforming growth factor-{beta}1, suggesting that it might affect remodeling by mechanisms distinct from glucocorticoids.


Key words: airway inflammation, asthma, phosphodiesterase inhibitors, remodeling, roflumilast, transforming growth factor-beta


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