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

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

Correspondence and requests for reprints should be addressed to Dr. Janette Burgess, Ph.D., Respiratory Research Group, Discipline of Pharmacology, Bosch Building, D05, University of Sydney, Sydney, NSW, Australia 2006. 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, but little is known about levels of endogenous antiangiogenic agents. Collagen IV is decreased in the airway basement membrane in asthma. It has six chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties.

Objectives: To study the expression of the noncollagenous domain-1 of the 3 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.

Key Words: asthma • angiogenesis • collagen • type IV collagen 3 chain

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Asthma is an inflammatory disease characterized by airway remodeling. A prominent feature of this remodeling is angiogenesis, which is an increase in the number and size of the blood vessels. The underlying mechanisms of angiogenesis remain unknown. What This Study Adds to the Field The molecule tumstatin is absent from the airways of patients with asthma. In vitro, tumstatin inhibited pulmonary endothelial cell tube formation in a dose-related manner, identifying a potential role in attenuating angiogenesis. In a murine model of chronic ovalbumin-induced allergic airways disease tumstatin inhibited angiogenesis and accumulation of vascular endothelial growth factor in the airway. Moreover, it attenuated the development of airway hyperresponsiveness and the accumulation of inflammatory cells and increases in IL-13 levels in the airways.