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Thorax 2005;60:106-113
© 2005 BMJ Publishing Group Ltd & British Thoracic Society

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

A R Kranenburg1, W I de Boer2, V K T Alagappan1, P J Sterk2, H S Sharma1

1 Department of Pharmacology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
2 Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Correspondence to:
Correspondence to:
H S Sharma
Institute of Pharmacology, Erasmus MC, University Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands;h.sharma{at}erasmusmc.nl

Background: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and angiogenesis in COPD.

Methods: The cellular expression pattern of VEGF, Flt-1, and KDR/Flk-1 was examined by immunohistochemistry in central and peripheral lung tissues obtained from ex-smokers with COPD (forced expiratory volume in 1 second (FEV1) <75% predicted; n = 14) or without COPD (FEV1 >85% predicted; n = 14). The immunohistochemical staining of each molecule was quantified using a visual scoring method with grades ranging from 0 (no) to 3 (intense).

Results: VEGF, Flt-1, and KDR/Flk-1 immunostaining was localised in vascular and airway smooth muscle (VSM and ASM) cells, bronchial, bronchiolar and alveolar epithelium, and macrophages. Pulmonary endothelial cells expressed Flt-1 and KDR/Flk-1 abundantly but not VEGF. Bronchial VEGF expression was higher in microvascular VSM cells and ASM cells of patients with COPD than in patients without COPD (1.7 and 1.6-fold, p<0.01, respectively). VEGF expression in intimal and medial VSM (1.7 and 1.3-fold, p<0.05) of peripheral pulmonary arteries associated with the bronchiolar airways was more intense in COPD, as was VEGF expression in the small pulmonary vessels in the alveolar region (1.5 and 1.7-fold, p<0.02). In patients with COPD, KDR/Flk-1 expression was enhanced in endothelial cells and in intimal and medial VSM (1.3, 1.9 and 1.5-fold, p<0.02) while endothelial Flt-1 expression was 1.7 times higher (p<0.03). VEGF expression was significantly increased in bronchiolar and alveolar epithelium as well as in bronchiolar macrophages (1.5-fold, p<0.001). The expression of VEGF in bronchial VSM and mucosal microvessels as well as bronchiolar epithelium was inversely correlated with FEV1 (r<–0.45; p<0.01).

Conclusions: VEGF and its receptors Flt-1 and KDR/Flk-1 may be involved in peripheral vascular and airway remodelling processes in an autocrine and/or paracrine manner. This system may also be associated with epithelial cell viability during airway wall remodelling in COPD.

Abbreviations: ASM, airway smooth muscle; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; TGF-ß1, transforming growth factor ß1; VEGF, vascular endothelial growth factor; VSM, vascular smooth muscle

Keywords: chronic obstructive pulmonary disease; vascular endothelial growth factor; angiogenesis


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