title: Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma.
abstract: RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition.
authors.affiliation: Respiratory Therapeutic Area (Discovery), Almirall R&D Center, Laureà Miró 408-410, Sant Feliu de Llobregat, Barcelona 08980, Spain jorgedealba@hotmail.com.
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.affiliation: Respiratory Therapeutic Area (Discovery), Almirall R&D Center, Laureà Miró 408-410, Sant Feliu de Llobregat, Barcelona 08980, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.affiliation: Respiratory Therapeutic Area (Discovery), Almirall R&D Center, Laureà Miró 408-410, Sant Feliu de Llobregat, Barcelona 08980, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Calama
authors.affiliation: Experimental Toxicology and Pathology, Almirall R&D Center, Laureà Miró 408-410, Sant Feliu de Llobregat, Barcelona 08980, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Domenech
authors.affiliation: Experimental Toxicology and Pathology, Almirall R&D Center, Laureà Miró 408-410, Sant Feliu de Llobregat, Barcelona 08980, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Prats
authors.affiliation: Union Chimique Belge Pharma Ltd, 208 Bath Road, Slough, Berkshire SL1 3WE, U.K.
authors.forename: Neil
authors.initials: N
authors.lastname: Gozzard
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D001249:Asthma / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007136:Immunoglobulins / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D010641:Phenotype; D011070:Poly I-C / Q000633:toxicity*; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000305:Adrenal Cortex Hormones; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1; D011070:Poly I-C
keywords: airway hyperresponsiveness; Freund’s complete adjuvant; house dust mite; neutrophilic asthma; poly(I:C); steroid resistance