title: TNF-α and Macrophages Are Critical for Respiratory Syncytial Virus-Induced Exacerbations in a Mouse Model of Allergic Airways Disease.
abstract: Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-α, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVA-sensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-α, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-α levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-α and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-α and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and.
authors.forename: Thi Hiep
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Maltby
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and Department of Respiratory and Sleep Medicine, Hunter New England Area Health Service, Newcastle, New South Wales 2305, Australia.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and.
authors.forename: Fiona
authors.initials: F
authors.lastname: Eyers
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and Department of Respiratory and Sleep Medicine, Hunter New England Area Health Service, Newcastle, New South Wales 2305, Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and Department of Respiratory and Sleep Medicine, Hunter New England Area Health Service, Newcastle, New South Wales 2305, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and paul.foster@newcastle.edu.au ming.yang@newcastle.edu.au.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2300, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales 2300, Australia; and paul.foster@newcastle.edu.au ming.yang@newcastle.edu.au.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology; D018932:Chemokine CCL2 / Q000032:analysis / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000503:physiopathology; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000502:physiology / Q000528:radiation effects; D012463:Saliva / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology*; D014466:Ultraviolet Rays
chemical_list: D000485:Allergens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D010047:Ovalbumin