title: Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.
abstract: Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR) to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1) were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.
authors.affiliation: Department of Pulmonary Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhuang-Gui
authors.initials: ZG
authors.lastname: Chen
authors.forename: Tian-Tuo
authors.initials: TT
authors.lastname: Zhang
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Li
authors.forename: Fen-Hua
authors.initials: FH
authors.lastname: Chen
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Zou
authors.forename: Jing-Zhi
authors.initials: JZ
authors.lastname: Ji
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor / Q000378:metabolism; D006706:Homeostasis; D006967:Hypersensitivity / Q000628:therapy*; D007249:Inflammation; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D039981:Pyroglyphidae / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000485:Allergens; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018793:Interleukin-13; D016210:Methacholine Chloride; D015847:Interleukin-4; D000094632:Thymic Stromal Lymphopoietin