help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Published ahead of print on October 29, 2009
Am. J. Respir. Crit. Care Med. 2009, doi:10.1164/rccm.200904-0631OC
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Burgess, J. K.
Right arrow Articles by Oliver, B. G
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burgess, J. K.
Right arrow Articles by Oliver, B. G

Submitted on April 30, 2009
Accepted on October 28, 2009

Reduction of Tumstatin in Asthmatic Airways Contributes to Angiogenesis, Inflammation and Hyperresponsiveness

Janette K. Burgess1*, Sarah Boustany2, Lyn M Moir1, Markus Weckmann2, Justine Y. Lau2, Karryn Grafton2, Melissa Baraket3, Philip M Hansbro4, Nicole G Hansbro4, Paul S Foster4, Judith L Black1, and Brian G Oliver1

1 Cooperative Research Centre for Asthma and Airways, The University of Sydney, Sydney, New South Wales, Australia; Discipline of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia; Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia, 2 Cooperative Research Centre for Asthma and Airways, The University of Sydney, Sydney, New South Wales, Australia; Discipline of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia, 3 Discipline of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia; Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia, 4 Cooperative Research Centre for Asthma and Airways, The University of Sydney, Sydney, New South Wales, Australia; Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia

* To whom correspondence should be addressed. E-mail: janette{at}pharmacol.usyd.edu.au.

Rationale: Angiogenesis is a prominent feature of remodeling in asthma. Many proangiogenic factors are up-regulated in asthma whereas little is known about levels of endogenous anti-angiogenic agents. Collagen IV is decreased in the airway basement membrane in asthma. It has six {alpha} chains, of which the non-collagenous domain-1 (NC1) domains have endogenous anti-angiogenic properties. Objectives: To study the expression of the NC1 domain of the {alpha}3 chain of collagen IV, tumstatin, in the airways of asthmatic and non-asthmatic volunteers and to examine the potential for tumstatin to regulate angiogenesis and inflammation. Methods: We have used immunohistochemistry (IHC) and dot blots to examine the expression of tumstatin in bronchial biopsies, BAL 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: We have made the novel observation that the level of tumstatin is markedly decreased (18 fold) in airways of asthmatic patients, but not those 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 interleukin 13. Conclusions: The observation that tumstatin is decreased in asthmatic airways and inhibits airway hyperresponsiveness and angiogenesis demonstrates the potential use of anti-angiogenic agents such as tumstatin as a therapeutic intervention in diseases which are characterized by aberrant angiogenesis and tissue remodeling, such as asthma.
Key words: asthma • angiogenesis • type IV collagen alpha3 chain • collagen






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2009 American Thoracic Society 		  New Orleans Int'l Conf