Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness

Am J Respir Crit Care Med. 2010 Jan 15;181(2):106-15. doi: 10.1164/rccm.200904-0631OC. Epub 2009 Oct 29.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Airway Remodeling / physiology
  • Animals
  • Asthma / pathology
  • Asthma / physiopathology*
  • Autoantigens / physiology*
  • Biopsy
  • Bronchi / blood supply*
  • Bronchi / pathology
  • Bronchial Hyperreactivity / pathology
  • Bronchial Hyperreactivity / physiopathology*
  • Bronchitis / pathology
  • Bronchitis / physiopathology*
  • Bronchoscopy
  • Cell Division / physiology
  • Collagen Type IV / metabolism
  • Collagen Type IV / physiology*
  • Disease Models, Animal
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Eosinophilia / pathology
  • Eosinophilia / physiopathology
  • Female
  • Humans
  • Interleukin-13 / metabolism
  • Lung / blood supply
  • Lung / pathology
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Middle Aged
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / physiopathology*
  • Respiratory Hypersensitivity / pathology
  • Respiratory Hypersensitivity / physiopathology
  • Vascular Endothelial Growth Factor A / metabolism
  • Young Adult


  • Autoantigens
  • Collagen Type IV
  • Interleukin-13
  • Vascular Endothelial Growth Factor A
  • type IV collagen alpha3 chain