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

Publisher:
American Thoracic Society
Publication Type:
Journal Article
Citation:
American Journal of Respiratory and Critical Care Medicine, 2010, 181 (2), pp. 106 - 115
Issue Date:
2010-01
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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 a chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties. Objectives: To study the expression of the noncollagenous domain-1 of the a3 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.
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