title: Endothelin-1 directs airway remodeling and hyper-reactivity in a murine asthma model.
abstract: BACKGROUND
  The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators.
  
  
  METHODS
  Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-β and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization.
  
  
  RESULTS
  Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1β levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes.
  
  
  CONCLUSIONS
  Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design.
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: L G
authors.initials: LG
authors.lastname: Gregory
authors.forename: C P
authors.initials: CP
authors.lastname: Jones
authors.forename: S A
authors.initials: SA
authors.lastname: Mathie
authors.forename: S
authors.initials: S
authors.lastname: Pegorier
authors.forename: C M
authors.initials: CM
authors.lastname: Lloyd
mesh_terms: D056151:Airway Remodeling / Q000235:genetics / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051899:Smad2 Protein / Q000235:genetics
chemical_list: D019332:Endothelin-1; D018836:Inflammation Mediators; D051899:Smad2 Protein; D010047:Ovalbumin
keywords: animal models; asthma; epithelium; innate immunity; remodeling