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

Burgess, JK; Boustany, S; Moir, LM; Weckmann, M; Lau, JY; Grafton, K; Baraket, M; Hansbro, PM; Hansbro, NG; Foster, PS; Black, JL; Oliver, BG

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

Burgess, JK Boustany, S Moir, LM Weckmann, M Lau, JY Grafton, K Baraket, M Hansbro, PM

Hansbro, NG Foster, PS Black, JL Oliver, BG

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Publication Type:: Journal Article
Citation:: American Journal of Respiratory and Critical Care Medicine, 2010, 181 (2), pp. 106 - 115
Issue Date:: 2010-01-15

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Field	Value	Language
dc.contributor.author	Burgess, JK	en_US
dc.contributor.author	Boustany, S	en_US
dc.contributor.author	Moir, LM	en_US
dc.contributor.author	Weckmann, M	en_US
dc.contributor.author	Lau, JY	en_US
dc.contributor.author	Grafton, K	en_US
dc.contributor.author	Baraket, M	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Hansbro, NG	en_US
dc.contributor.author	Foster, PS	en_US
dc.contributor.author	Black, JL	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.date.issued	2010-01-15	en_US
dc.identifier.citation	American Journal of Respiratory and Critical Care Medicine, 2010, 181 (2), pp. 106 - 115	en_US
dc.identifier.issn	1073-449X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/28544
dc.description.abstract	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 α chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties. Objectives: To study the expression of the noncollagenous domain-1 of the α3 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 murinemodel 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.	en_US
dc.relation.ispartof	American Journal of Respiratory and Critical Care Medicine	en_US
dc.relation.isbasedon	10.1164/rccm.200904-0631OC	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Endothelial Cells	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Asthma	en_US
dc.subject.mesh	Bronchial Hyperreactivity	en_US
dc.subject.mesh	Bronchitis	en_US
dc.subject.mesh	Respiratory Hypersensitivity	en_US
dc.subject.mesh	Eosinophilia	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Neovascularization, Pathologic	en_US
dc.subject.mesh	Vascular Endothelial Growth Factor A	en_US
dc.subject.mesh	Collagen Type IV	en_US
dc.subject.mesh	Interleukin-13	en_US
dc.subject.mesh	Autoantigens	en_US
dc.subject.mesh	Microscopy, Fluorescence	en_US
dc.subject.mesh	Bronchoscopy	en_US
dc.subject.mesh	Biopsy	en_US
dc.subject.mesh	Cell Division	en_US
dc.subject.mesh	Adolescent	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Young Adult	en_US
dc.subject.mesh	Airway Remodeling	en_US
dc.title	Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	181	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	181	en_US

Abstract:

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 α chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties. Objectives: To study the expression of the noncollagenous domain-1 of the α3 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 murinemodel 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.

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http://hdl.handle.net/10453/28544