title: Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness.
abstract: BACKGROUND
  Angiogenesis is a prominent feature of remodeling in asthma. Many proangiogenic factors are up-regulated in asthma, but little is known about levels of endogenous antiangiogenic agents. Collagen IV is decreased in the airway basement membrane in asthma. It has six alpha chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties.
  
  
  OBJECTIVE
  To study the expression of the noncollagenous domain-1 of the alpha3 chain of collagen IV, tumstatin, in the airways of subjects with and without asthma and to examine the potential for tumstatin to regulate angiogenesis and inflammation.
  
  
  METHODS
  We used immunohistochemistry and dot blots to examine the expression of tumstatin in bronchial biopsies, bronchoalveolar lavage fluid, and serum. We then used an in vitro angiogenesis assay and a murine model of allergic airways disease to explore tumstatin's biological function.
  
  
  RESULTS
  The level of tumstatin is decreased 18-fold in the airways of patients with asthma but not in subjects without asthma, including those with chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis. In vitro, recombinant tumstatin inhibited primary pulmonary endothelial cell tube formation. In a mouse model of chronic allergic airways disease, tumstatin suppressed angiogenesis, airway hyperresponsiveness, inflammatory cell infiltration, and mucus secretion and decreased levels of vascular endothelial growth factor and IL-13.
  
  
  CONCLUSIONS
  The observation that tumstatin is decreased in asthmatic airways and inhibits airway hyperresponsiveness and angiogenesis demonstrates the potential use of antiangiogenic agents such as tumstatin as a therapeutic intervention in diseases that are characterized by aberrant angiogenesis and tissue remodeling, such as asthma.
authors.affiliation: Respiratory Research Group, Discipline of Pharmacology, Bosch Building, D05, University of Sydney, Sydney, NSW, Australia 2006. janette@pharmacol.usyd.edu.au
authors.forename: Janette K
authors.initials: JK
authors.lastname: Burgess
authors.forename: Sarah
authors.initials: S
authors.lastname: Boustany
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Moir
authors.forename: Markus
authors.initials: M
authors.lastname: Weckmann
authors.forename: Justine Y
authors.initials: JY
authors.lastname: Lau
authors.forename: Karryn
authors.initials: K
authors.lastname: Grafton
authors.forename: Melissa
authors.initials: M
authors.lastname: Baraket
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Judith L
authors.initials: JL
authors.lastname: Black
authors.forename: Brian G
authors.initials: BG
authors.lastname: Oliver
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling / Q000502:physiology; D000818:Animals; D001249:Asthma / Q000473:pathology / Q000503:physiopathology*; D001324:Autoantigens / Q000502:physiology*; D001706:Biopsy; D001980:Bronchi / Q000098:blood supply* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000473:pathology / Q000503:physiopathology*; D001991:Bronchitis / Q000473:pathology / Q000503:physiopathology*; D001999:Bronchoscopy; D002455:Cell Division / Q000502:physiology; D024141:Collagen Type IV / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D004802:Eosinophilia / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D012130:Respiratory Hypersensitivity / Q000473:pathology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D018793:Interleukin-13; D042461:Vascular Endothelial Growth Factor A; C057112:type IV collagen alpha3 chain