title: Nerve growth factor induces type III collagen production in chronic allergic airway inflammation.
abstract: BACKGROUND
  Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood.
  
  
  OBJECTIVE
  We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation.
  
  
  METHODS
  Antibody-blocking experiments were performed in an in vivo model for chronic allergic airway inflammation (allergic asthma), which is accompanied by matrix deposition in the subepithelial compartment of the airways, to study the profibrotic effect of NGF. The signaling pathways were delineated with in vivo and in vitro studies in primary lung fibroblasts.
  
  
  RESULTS
  Functional blocking of NGF in chronically affected mice markedly prevented subepithelial fibrosis. Transgenic overexpression of NGF in murine airways resulted in altered airway wall morphology with increased peribronchial collagen deposition and impaired lung physiology in the absence of inflammation. NGF exerted a direct effect on collagen expression in murine lung fibroblasts, which was mainly mediated through the activation of the receptor tropomyosin-related kinase A. NGF-induced collagen expression was dependent on downstream activation of p38 mitogen-activated protein kinase independent of the TGF-β1/mothers against decapentaplegic homolog (SMAD) pathway.
  
  
  CONCLUSIONS
  The results of this study demonstrate that NGF exerts profibrotic activities in the airways by inducing type III collagen production in fibroblasts independently of TGF-β1.
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Medical Faculty-Philipps University of Marburg, Marburg, Germany.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Kılıç
authors.forename: Sanchaita Sriwal
authors.initials: SS
authors.lastname: Sonar
authors.forename: Ali Oender
authors.initials: AO
authors.lastname: Yildirim
authors.forename: Heinz
authors.initials: H
authors.lastname: Fehrenbach
authors.forename: Wolfgang Andreas
authors.initials: WA
authors.lastname: Nockher
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D024061:Collagen Type III / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006967:Hypersensitivity / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D024061:Collagen Type III; D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020932:Nerve Growth Factor