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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Airwaves

Wisia Wedzicha
Thorax 2005 60: 87. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Paredi, P, Barnes, P J (2009). The airway vasculature: recent advances and clinical implications. Thorax 64: 444-450 [Abstract] [Full Text]  
• Simcock, D. E., Kanabar, V., Clarke, G. W., Mahn, K., Karner, C., O'Connor, B. J., Lee, T. H., Hirst, S. J. (2008). Induction of Angiogenesis by Airway Smooth Muscle From Patients with Asthma. Am. J. Respir. Crit. Care Med. 178: 460-468 [Abstract] [Full Text]  
• Edirisinghe, I., Yang, S.-R., Yao, H., Rajendrasozhan, S., Caito, S., Adenuga, D., Wong, C., Rahman, A., Phipps, R. P., Jin, Z.-G., Rahman, I. (2008). VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. FASEB J. 22: 2297-2310 [Abstract] [Full Text]  
• Zanini, A., Chetta, A., Olivieri, D. (2008). Review: Therapeutic perspectives in bronchial vascular remodeling in COPD. Ther Adv Respir Dis 2: 179-187 [Abstract]  
• Cheng, S-L, Wang, H-C, Yu, C-J, Yang, P-C (2008). Increased expression of placenta growth factor in COPD. Thorax 63: 500-506 [Abstract] [Full Text]  
• Hasaneen, N. A., Zucker, S., Lin, R. Z., Vaday, G. G., Panettieri, R. A., Foda, H. D. (2007). Angiogenesis is induced by airway smooth muscle strain. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L1059-L1068 [Abstract] [Full Text]  
• Demiralay, R., Gursan, N., Erdem, H. (2007). Regulation of nicotine-induced apoptosis of pulmonary artery endothelial cells by treatment of N-acetylcysteine and vitamin E. Hum Exp Toxicol 26: 595-602 [Abstract]  
• Pinto-Plata, V., Toso, J., Lee, K., Park, D., Bilello, J., Mullerova, H., De Souza, M. M, Vessey, R., Celli, B. (2007). Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax 62: 595-601 [Abstract] [Full Text]  
• Bergeron, C., Tulic, M. K., Hamid, Q. (2007). Tools used to measure airway remodelling in research. Eur Respir J 29: 596-604 [Abstract] [Full Text]  
• Chan, V., Burgess, J. K., Ratoff, J. C., O'Connor, B. J., Greenough, A., Lee, T. H., Hirst, S. J. (2006). Extracellular Matrix Regulates Enhanced Eotaxin Expression in Asthmatic Airway Smooth Muscle Cells. Am. J. Respir. Crit. Care Med. 174: 379-385 [Abstract] [Full Text]  
• Postma, D. S., Timens, W. (2006). Remodeling in asthma and chronic obstructive pulmonary disease.. Proc Am Thorac Soc 3: 434-439 [Abstract] [Full Text]  
• Fabbri, L. M., Luppi, F., Beghe, B., Rabe, K. F. (2006). Update in chronic obstructive pulmonary disease 2005.. Am. J. Respir. Crit. Care Med. 173: 1056-1065 [Full Text]  
• Knox, A J, Stocks, J, Sutcliffe, A (2005). Angiogenesis and vascular endothelial growth factor in COPD. Thorax 60: 88-89 [Full Text]