title: Inhaled dsRNA and rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma.
abstract: BACKGROUND
  Rhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral infection-induced exacerbations.
  
  
  METHODS
  Allergic mice were challenged with OVA followed by three daily intranasal challenges with dsRNA or saline. Bronchoalveolar lavage fluid (BALF) was analysed for total protein, lactate dehydrogenase (LDH), CXCL1/KC, CCL2/MCP-1 and differential cell counts. Lung tissue histology, neutrophils and TSLP, TNF-α, IFN-β and IFN-λ mRNA were examined. Alternatively, allergen-challenged mice received intranasal rhinovirus-(RV)-1B followed by lung TSLP immunostaining.
  
  
  RESULTS
  In mice with allergic airway inflammation, dsRNA challenges caused a significant exacerbation increasing lung tissue inflammation score and tissue neutrophilia. Bronchoalveolar lavage fluid neutrophils, total protein, LDH, CXCL1/KC and CCL2/MCP-1 were also increased (P < 0.01), and so were lung tissue expressions of TNF-α, IFN-λ and TSLP (P < 0.01), but IFN-β was not increased. TSLP, IFN-λ and LDH were not increased by allergen or dsRNA challenges alone, but increased exclusively at exacerbations. RV1B infection-induced exacerbation also increased lung tissue TSLP (P < 0.05).
  
  
  CONCLUSIONS
  dsRNA-induced exacerbation in mice with experimental asthma involved general inflammation, cytokines and interferons, in agreement with previous observations in exacerbating human asthma. Additionally, both dsRNA and RV1B infection increased lung TSLP exclusively at exacerbations. Our data suggest that dsRNA challenges superimposed on allergic inflammation are suited for pharmacological studies of asthma exacerbations including the regulation of lung tissue TSLP, TNF-α, IFN-β and IFN-λ.
authors.affiliation: Unit of Respiratory Immunopharmacology, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Mahmutovic-Persson
authors.forename: H
authors.initials: H
authors.lastname: Akbarshahi
authors.forename: N W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: N
authors.initials: N
authors.lastname: Glanville
authors.forename: S L
authors.initials: SL
authors.lastname: Johnston
authors.forename: A
authors.initials: A
authors.lastname: Brandelius
authors.forename: L
authors.initials: L
authors.lastname: Uller
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000276:immunology*; D012229:Rhinovirus / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D012330:RNA, Double-Stranded; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010047:Ovalbumin; D000094632:Thymic Stromal Lymphopoietin
keywords: TLR3; allergy; asthma; exacerbation; neutrophils