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.
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.
Authors: Gloria S Forkuo; Hosu Kim; Vaidehi J Thanawala; Nour Al-Sawalha; Daniel Valdez; Radhika Joshi; Sergio Parra; Tonio Pera; Patricia A Gonnella; Brian J Knoll; Julia K L Walker; Raymond B Penn; Richard A Bond Journal: Am J Respir Cell Mol Biol Date: 2016-08 Impact factor: 6.914
Authors: Paul S Foster; Steven Maltby; Helene F Rosenberg; Hock L Tay; Simon P Hogan; Adam M Collison; Ming Yang; Gerard E Kaiko; Philip M Hansbro; Rakesh K Kumar; Joerg Mattes Journal: Immunol Rev Date: 2017-07 Impact factor: 12.988
Authors: Jessica S Siegle; Nicole Hansbro; Cristan Herbert; Helene F Rosenberg; Joseph B Domachowske; Kelly L Asquith; Paul S Foster; Rakesh K Kumar Journal: Respir Res Date: 2010-02-03
Authors: Joerg Mattes; Adam Collison; Maximilian Plank; Simon Phipps; Paul S Foster Journal: Proc Natl Acad Sci U S A Date: 2009-10-20 Impact factor: 11.205