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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 517-525, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.4474

Enhanced Expression of Fibroblast Growth Factors and Receptor FGFR-1 during Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Andor R. Kranenburg, Willem I. de Boer, J. Han J.M. van Krieken, Wolter J. Mooi, Jane E. Walters, Pramod R. Saxena, Peter J. Sterk and Hari S. Sharma

Department of Pharmacology, Erasmus University Medical Center, Rotterdam; Departments of Pulmonology and Pathology, Leiden University Medical Center, Leiden; Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands; and School of Biological Molecular Sciences, Oxford Brookes University, Oxford, United Kingdom

Address correspondence to: Hari S. Sharma, M.Phil., Ph.D., Institute of Pharmacology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: sharma{at}farma.fgg.eur.nl

Important characteristics of chronic obstructive pulmonary disease (COPD) include airway and vascular remodeling, the molecular mechanisms of which are poorly understood. We assessed the role of fibroblast growth factors (FGF) in pulmonary vascular remodeling by examining the expression pattern of FGF-1, FGF-2, and the FGF receptor (FGFR-1) in peripheral area of lung tissues from patients with COPD (FEV1 <= 75%; n = 15) and without COPD (FEV1 >= 85%; n = 13). Immunohistochemical staining results were evaluated by digital video image analysis as well as by manual scoring. FGF-1 and FGFR-1 were detected in vascular smooth muscle (VSM), airway smooth muscle, and airway epithelial cells. FGF-2 was localized in the cytoplasm of airway epithelium and in the nuclei of airway smooth muscle, VSM, and endothelial cells. In COPD cases, an unequivocal increase in FGF-2 expression was observed in VSM (3-fold, P = 0.001) and endothelium (2-fold, P = 0.007) of small pulmonary vessels with a luminal diameter under 200 µm. In addition, FGFR-1 levels were elevated in the intima (1.5-fold, P = 0.05). VSM cells of large (> 200 µm) pulmonary vessels showed increased staining for FGF-1 (1.6-fold, P < 0.03) and FGFR-1 (1.4-fold, P < 0.04) in COPD. Pulmonary vascular remodeling, assessed as the ratio of {alpha}-smooth muscle actin staining and vascular wall area with the lumen diameter, was increased in large vessels of patients with COPD (P = 0.007) and was inversely correlated with FEV1 values (P < 0.007). Our results suggest an autocrine role of the FGF–FGFR-1 system in the pathogenesis of COPD-associated vascular remodeling.

Abbreviations: chronic obstructive pulmonary disease, COPD • forced expiratory volume in one second, FEV1 • fibroblast growth factors, FGF • fibroblast growth factor receptor, FGFR • forced vital capacity, FVC • inside diameter, ID • carbon monoxide diffusion, Kco • platelet-derived growth factor, PDGF • {alpha}-smooth muscle actin, {alpha}-SMA • vascular smooth muscle, VSM • vascular wall, VW




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