Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma.
BACKGROUND
In a mouse model of mild chronic asthma, both inflammation and remodelling can be suppressed by dexamethasone (a glucocorticoid) and roflumilast (a selective phosphodiesterase-4 inhibitor).


OBJECTIVE
To better understand the underlying molecular mechanisms, we investigated the effects of treatment on airway expression of inflammation-related cytokines, as well as on epithelial expression of growth factors.


METHODS
BALB/c mice systemically sensitized to ovalbumin were challenged with aerosolized antigen for 6 weeks and treated with roflumilast or dexamethasone during the final 2 weeks. Expression of mRNA, for a variety of cytokines and growth factors, was assessed in selectively dissected proximal airways or in airway epithelium obtained by laser capture microdissection.


RESULTS
In the airway wall of vehicle-treated challenged animals, there was significantly elevated expression of mRNA for a variety of pro-inflammatory and T helper type 2 cytokines, as well as for IFN-gamma. All these cytokines were suppressed by dexamethasone. Treatment with roflumilast reduced expression of IL-17A, TNF-alpha, granulocyte-macrophage colony-stimulating factor and IL-6, but did not inhibit other cytokines. Both drugs suppressed the enhanced expression of mRNA for growth factors such as TGF-beta1 and FGF-2 in airway epithelium.


CONCLUSIONS
Whereas dexamethasone non-specifically inhibits numerous mediators involved in inflammation and the immune response, roflumilast selectively inhibits a subset of pro-inflammatory cytokines and growth factors. These mediators and/or the cells that produce them may have critical roles in the pathogenesis of the lesions of chronic asthma.
Herbert
C
C
Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Hettiaratchi
A
A
Webb
D C
DC
Thomas
P S
PS
Foster
P S
PS
Kumar
R K
RK
D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D002908:Chronic Disease; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms
D000631:Aminopyridines; D018927:Anti-Asthmatic Agents; D001549:Benzamides; D003521:Cyclopropanes; D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D003907:Dexamethasone