RESUMO
Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-ß reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/ß receptor (IFNAR1-/-) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-ß therapy may protect.
Assuntos
Corticosteroides/farmacologia , Carga Bacteriana/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Muco/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Rhinovirus/efeitos dos fármacos , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/imunologia , Animais , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Linhagem Celular , Fluticasona/administração & dosagem , Fluticasona/imunologia , Fluticasona/farmacologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/virologia , Camundongos Knockout , Muco/microbiologia , Muco/virologia , Infecções por Picornaviridae/prevenção & controle , Infecções por Picornaviridae/virologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/virologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Rhinovirus/imunologia , Rhinovirus/fisiologiaRESUMO
BACKGROUND: Allergen exposure via the respiratory tract and in particular via the nasal mucosa boosts systemic allergen-specific IgE production. Intranasal corticosteroids (INCS) represent a first line treatment of allergic rhinitis but their effects on this boost of allergen-specific IgE production are unclear. AIM: Here we aimed to determine in a double-blind, placebo-controlled study whether therapeutic doses of an INCS preparation, i.e., nasal fluticasone propionate, have effects on boosts of allergen-specific IgE following nasal allergen exposure. METHODS: Subjects (n = 48) suffering from grass and birch pollen allergy were treated with daily fluticasone propionate or placebo nasal spray for four weeks. After two weeks of treatment, subjects underwent nasal provocation with either birch pollen allergen Bet v 1 or grass pollen allergen Phl p 5. Bet v 1 and Phl p 5-specific IgE, IgG1-4, IgM and IgA levels were measured in serum samples obtained at the time of provocation and one, two, four, six and eight weeks thereafter. RESULTS: Nasal allergen provocation induced a median increase to 141.1% of serum IgE levels to allergens used for provocation but not to control allergens 4 weeks after provocation. There were no significant differences regarding the boosts of allergen-specific IgE between INCS- and placebo-treated subjects. CONCLUSION: In conclusion, the application of fluticasone propionate had no significant effects on the boosts of systemic allergen-specific IgE production following nasal allergen exposure. TRIAL REGISTRATION: http://clinicaltrials.gov/NCT00755066.
