Published ahead of print on April 26, 2007, doi:10.1164/rccm.200701-042OC
Am. J. Respir. Crit. Care Med., Volume 176, Number 2, July 2007, 146-153
A more recent version of this article appeared on July 15, 2007
Submitted on January 9, 2007
Accepted on April 26, 2007
Pro-angiogenic Activity in Bronchoalveolar Lavage Fluid from Asthmatics
David E Simcock1, Varsha Kanabar1, Graham W Clarke1, Brian J O'Connor1, Tak H Lee1, and Stuart J Hirst1*
1 MRC & Asthma UK Centre in Allergic Mechanisms of Asthma and Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom
* To whom correspondence should be addressed. 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 if pro-angiogenic mediators are elevated in bronchoalveolar lavage fluid (BALf)from asthmatics and if this translated to induction of angiogenesis.
Methods: Angiogenic activity in BALf from 12 healthy, non-atopic subjects and 10 mild atopic asthmatics was evaluated by examining tubule formation at 11-days in co-cultures of human endothelial cells with dermal fibroblasts. Vascular structures were visualised by anti-CD31 labeling and quantified by image analysis. Angiogenic growth factors in BALf from healthy and asthmatic subjects were identified using RayBio Antibody Angiogenesis Arrays and by ELISA.
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. Similarly, levels of pro-angiogenic growth factors (angiogenin, VEGF, MCP-1) were increased ~2.5-fold
(p<0.05) in BALf from asthmatics, whereas anti-angiogenic factors (endostatin, Ang-2)were unchanged. A blocking anti-VEGF antibody abolished tubule formation induced by
BALf from either healthy or asthmatic subjects (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 asthmatics but not healthy subjects is functionally active in promoting angiogenesis in vitro. The pro-angiogenic capacity of BALf from asthmatics 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 remodelling; angiogenesis; asthma; bronchoalveolar lavage fluid, vascular endothelial growth factor
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