Boer, W.I. de

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

2005-02-01T00:00:00Z

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 (FEV(1)) <75% predicted; n = 14) or without COPD (FEV(1) >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 FEV(1) (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.

Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease (Article)

2002-01-01T00:00:00Z

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 (FEV(1) < or = 75%; n = 15) and without COPD (FEV(1) > or = 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 micro m. In addition, FGFR-1 levels were elevated in the intima (1.5-fold, P = 0.05). VSM cells of large (> 200 micro m) 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 FEV(1) values (P < 0.007). Our results suggest an autocrine role of the FGF-FGFR-1 system in the pathogenesis of COPD-associated vascular remodeling.

Cytokines and therapy in COPD: a promising combination? (Article)

2002-01-01T00:00:00Z

COPD is a major health problem, with patients showing a progressively declining, largely irreversible, change in lung function. This is associated with chronic airways inflammation and structural remodeling, including loss of alveolar walls, and goblet cell metaplasia with mucus hypersecretion. Inflammatory cells may contribute to the airway remodeling via secretion of proteases, fibrotic or mitogenic growth factors, and cytokines. In turn, airway remodeling may contribute to the clinical symptoms of COPD. Currently available therapies are directed to improvement of clinical symptoms and reduction of the airways inflammation. The commonly used glucocorticosteroids are expected to reduce the inflammation by acting on kinases or transcription factors necessary for expression of pro-inflammatory cytokines or chemokines. However, several long-term and short-term studies showed that glucocorticosteroids are rather ineffective in improving lung function and reducing the airway inflammation in patients with COPD. New therapeutic strategies may reduce the inflammation and alleviate the clinical symptoms of COPD. Tumor necrosis factor-alpha, interleukin-8, and monocyte chemoattractant protein-1 are important chemotactic proteins for macrophages and neutrophils, the predominant inflammatory cells associated with COPD. As lung levels of these cytokines are higher in COPD compared to non-COPD patients, they may represent targets for novel therapies.

Growth factors in bladder epithelium : a study on the expression and functions of growth factors in mouse urothelium (Doctoral Thesis)

1995-01-11T00:00:00Z

The urogenital tract is one of the major excretory paths for small metabolites and ions. The excreted liquid, urine, is produced by the kidneys, flows through the ureters into the urinary bladder and is finally excreted through the urethra. The mammalian urinary bladder has the important capacity to retain urine for some time. Normally, the bladder is resistant to toxic effects of products in the urine. But after damage to the epithelium of the bladder, bladder epithelial cells may become vulnerable to xenotoxic agents and potential toxic metabolites in the urine. In general, this damage will be repaired by physiological processes. During neoplasia, e.g. in transitional cell carcinoma, aberrations in physiologically regulated processes occur. This thesis focuses on protein factors that may be involved in the physiology of transitional epithelium of the mouse bladder, and their specific functions. The following paragraphs highlight subsequently the structure and function of the bladder (§ 1) the physiology and causes of abnormal growth of the urothelium (§2), proteins that have been shown to be involved in the physiology of normal and tumour cells (§3), what is currently known about these proteins with respect to the bladder (§3.5), and finally the aim of the thesis (§4).