title: Mechanistic insights into the contribution of epithelial damage to airway remodeling. Novel therapeutic targets for asthma.
abstract: It has been suggested that an inherent airway epithelial repair defect is the root cause of airway remodeling in asthma. However, the relationship between airway epithelial injury and repair, airway remodeling, and airway hyperresponsiveness (AHR) has not been directly examined. We investigated the contribution of epithelial damage and repair to the development of airway remodeling and AHR using a validated naphthalene (NA)-induced murine model of airway injury. In addition, we examined the endogenous versus exogenous role of the epithelial repair peptide trefoil factor 2 (TFF2) in disease pathogenesis. A single dose of NA (200 mg/kg in 10 ml/kg body weight corn oil [CO] vehicle, intraperitoneally) was administered to mice. Control mice were treated with CO (10 ml/kg body weight, intraperitoneally). At 12, 24, 48, and 72 hours after NA or CO injection, AHR and various measures of airway remodeling were examined by invasive plethysmography and morphometric analyses, respectively. TFF2-deficient mice and intranasal treatment were used to examine the role of the epithelial repair peptide. NA treatment induced denudation and apoptosis of airway epithelial cells, goblet cell metaplasia, elevated AHR, and increased levels of endogenous TFF2. Airway epithelial changes peaked at 12 hours after NA treatment, whereas airway remodeling changes were observed from 48 hours. TFF2 was protective against epithelial damage and induced remodeling and was found to mediate organ protection via a platelet-derived growth factor-associated mechanism. Our findings directly demonstrate the contribution of epithelial damage to airway remodeling and AHR and suggest that preventing airway epithelial damage and promoting epithelial repair may have therapeutic implications for asthma treatment.
authors: 1 Department of Allergy and Immune Disorders, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
authors: Simon G
authors: SG
authors: Royce
authors: Xuelei
authors: X
authors: Li
authors: Stephanie
authors: S
authors: Tortorella
authors: Liana
authors: L
authors: Goodings
authors: Bryna S M
authors: BS
authors: Chow
authors: Andrew S
authors: AS
authors: Giraud
authors: Mimi L K
authors: ML
authors: Tang
authors: Chrishan S
authors: CS
authors: Samuel
mesh_terms: D056151:Airway Remodeling / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001249:Asthma / Q000235:genetics / Q000503:physiopathology*; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D008168:Lung / Q000503:physiopathology; D008679:Metaplasia / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D000071164:Trefoil Factor-2; D015854:Up-Regulation / Q000235:genetics
chemical_list: D010455:Peptides; D010982:Platelet-Derived Growth Factor; C000604007:TFF2 protein, human; D053773:Transforming Growth Factor beta1; D000071164:Trefoil Factor-2; D055513:Connective Tissue Growth Factor; D003094:Collagen