TY - JOUR
T1 - Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma
AU - Kumar, Rakesh K.
AU - Herbert, Cristan
AU - Thomas, Paul S.
AU - Wollin, Lutz
AU - Beume, Rolf
AU - Yang, Ming
AU - Webb, Dianne C.
AU - Foster, Paul S.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a nonselective 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 with 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-β1, and epithelial cytoplasmic immunoreactivity for nuclear factor-κB. 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-β1, suggesting that it might affect remodeling by mechanisms distinct from glucocorticoids.
AB - Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a nonselective 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 with 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-β1, and epithelial cytoplasmic immunoreactivity for nuclear factor-κB. 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-β1, suggesting that it might affect remodeling by mechanisms distinct from glucocorticoids.
UR - http://www.scopus.com/inward/record.url?scp=0141519355&partnerID=8YFLogxK
U2 - 10.1124/jpet.103.053819
DO - 10.1124/jpet.103.053819
M3 - Article
SN - 0022-3565
VL - 307
SP - 349
EP - 355
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -