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Published ahead of print on April 26, 2007, doi:10.1164/rccm.200701-042OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 146-153, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200701-042OC

Original Article

Proangiogenic Activity in Bronchoalveolar Lavage Fluid from Patients with Asthma

David E. Simcock1, Varsha Kanabar1, Graham W. Clarke1, Brian J. O'Connor1, Tak H. Lee1 and Stuart J. Hirst1

1 Division of Asthma, Allergy, and Lung Biology, King's College London, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., King's College London, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Asthma, Allergy & Lung Biology, Thomas Guy House, Guy's Hospital Campus, London SE1 9RT, UK. E-mail: stuart.hirst{at}kcl.ac.uk

Rationale: Asthmatic airways have an increased number and size of vascular structures, which contribute to airflow obstruction and hyperresponsiveness.

Objectives: We examined whether proangiogenic mediators are elevated in bronchoalveolar lavage fluid (BALF) from subjects with asthma and if this translated to induction of angiogenesis.

Methods: Angiogenic activity in BALF from 12 healthy, nonatopic subjects and 10 atopic subjects with mild asthma was evaluated by examining tubule formation at 11 days in cocultures of human endothelial cells with dermal fibroblasts. Vascular structures were visualized by anti-CD31 labeling and quantified by image analysis. Angiogenic growth factors in BALF from healthy subjects and subjects with asthma were identified using antibody arrays and by ELISA.

Measurements and Main Results: Angiogenic activity induced by BALF from healthy subjects was not different from basal tubule formation (p > 0.05). However, induction of tubular structures by asthmatic BALF was 2.5-fold greater (p < 0.001) compared with healthy samples. Similarly, levels of proangiogenic growth factors (angiogenin, vascular endothelial growth factor [VEGF], monocyte chemotactic protein-1) were increased approximately 2.5-fold (p < 0.05) in BALF from subjects with asthma, whereas antiangiogenic factors (endostatin, Ang-2) were unchanged. A blocking anti-VEGF antibody abolished tubule formation induced by BALF from either healthy subjects or subjects with asthma (p < 0.01). Immunodepletion of VEGF had no effect on basal tubule formation induced by healthy BALF but abrogated enhanced tubule formation by asthmatic BALF (p < 0.01).

Conclusions: BALF collected from subjects with asthma but not healthy subjects is functionally active in promoting angiogenesis in vitro. The proangiogenic capacity of BALF from subjects with asthma resides in elevated VEGF derived from asthmatic airways. This observation supports VEGF as a key factor in vascular remodeling in asthma.

Key Words: airway wall vascular remodeling • angiogenesis • asthma • bronchoalveolar lavage fluid • vascular endothelial growth factor


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
The contribution of the airway microvascular bed to asthma phenotype has not been fully elucidated.

What This Study Adds to the Field
VEGF is the major component in bronchoalveolar lavage fluid from subjects with asthma promoting in vitro angiogenesis, underscoring its importance in asthma pathogenesis.

 



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