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

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.

[1]  W. Thurlbeck,et al.  Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health Nocturnal Oxygen Therapy Trial , 2004, Lung.

[2]  N. Ambalavanan,et al.  Hypoxia-Induced Release of Peptide Growth Factors from Neonatal Porcine Pulmonary Artery Smooth Muscle Cells , 1999, Neonatology.

[3]  V. Peinado,et al.  Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. , 1999, American journal of respiratory and critical care medicine.

[4]  M. Selman,et al.  Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts. , 1999, American journal of respiratory cell and molecular biology.

[5]  W. Steudel,et al.  alpha-smooth-muscle actin and microvascular precursor smooth-muscle cells in pulmonary hypertension. , 1999, American journal of respiratory cell and molecular biology.

[6]  S. Bryant,et al.  Vascular remodeling in response to altered blood flow is mediated by fibroblast growth factor-2. , 1999, Circulation research.

[7]  S. White,et al.  Microvessel precursor smooth muscle cells express head-inserted smooth muscle myosin heavy chain (SM-B) isoform in hyperoxic , 1999, Cell and Tissue Research.

[8]  J. Fallon,et al.  Fibroblast growth factors as multifunctional signaling factors. , 1999, International review of cytology.

[9]  P. Hiemstra,et al.  Transforming Growth Factor β1 and Recruitment of Macrophages and Mast Cells in Airways in Chronic Obstructive Pulmonary Disease , 1998 .

[10]  P. Barnes,et al.  Pharmacology of airway smooth muscle. , 1998, American journal of respiratory and critical care medicine.

[11]  P. Barnes,et al.  Chronic obstructive pulmonary disease: new opportunities for drug development. , 1998, Trends in pharmacological sciences.

[12]  R. Irwin,et al.  Chronic obstructive pulmonary disease , 1998, The Lancet.

[13]  T. Sasaki,et al.  Basic fibroblast growth factor expression precedes flow-induced arterial enlargement. , 1998, The Journal of surgical research.

[14]  V. Peinado,et al.  Endothelial dysfunction in pulmonary arteries of patients with mild COPD. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[15]  S. Werner,et al.  Keratinocyte growth factor: a unique player in epithelial repair processes. , 1998, Cytokine & growth factor reviews.

[16]  L. Fabbri,et al.  CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[17]  P. Jeffery,et al.  Structural and inflammatory changes in COPD: a comparison with asthma. , 1998, Thorax.

[18]  P. Sterk,et al.  Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages. , 1997, The American journal of pathology.

[19]  S. Shousha,et al.  Down-regulation of a novel form of fibroblast growth factor receptor 1 in human breast cancer. , 1997, British Journal of Cancer.

[20]  M. Selman,et al.  Upregulation of acidic fibroblast growth factor during development of experimental lung fibrosis. , 1997, The American journal of physiology.

[21]  P. D. Henry,et al.  Atherosclerosis as a microvascular disease: impaired angiogenesis mediated by suppressed basic fibroblast growth factor expression. , 1997, Proceedings of the Association of American Physicians.

[22]  S. Shousha,et al.  The location of acidic fibroblast growth factor in the breast is dependent on the activity of proteases present in breast cancer tissue. , 1997, British Journal of Cancer.

[23]  J. Pickering,et al.  Coordinated effects of fibroblast growth factor-2 on expression of fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases by human vascular smooth muscle cells. Evidence for repressed collagen production and activated degradative capacity. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[24]  M. Eldar,et al.  The role of insulin-like and basic fibroblast growth factors on ischemic and infarcted myocardium: a mini review. , 1997, International journal of cardiology.

[25]  J. Rosenbaum,et al.  Altered immunohistochemical localization of basic fibroblast growth factor after bleomycin-induced lung injury. , 1997, Growth factors.

[26]  S. Holgate.  Asthma: a dynamic disease of inflammation and repair. , 1997, Ciba Foundation symposium.

[27]  P. Maher,et al.  Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. , 1996, Brain research. Molecular brain research.

[28]  M. B. King,et al.  Pathogenesis of obliterative bronchiolitis. Possible roles of platelet-derived growth factor and basic fibroblast growth factor. , 1995, Transplantation.

[29]  D Ros,et al.  Pulmonary vascular abnormalities and ventilation-perfusion relationships in mild chronic obstructive pulmonary disease. , 1994, American journal of respiratory and critical care medicine.

[30]  P. Hall,et al.  Immunolocalization of fibroblast growth factor receptor 1 and its ligands in human tissues. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[31]  J E Cotes,et al.  Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. , 1993, The European respiratory journal. Supplement.

[32]  M. Sporn,et al.  Transforming Growth Factor‐β , 1990 .

[33]  J. Hogg,et al.  Pulmonary vascular structure and function in chronic obstructive pulmonary disease. , 1988, Thorax.

[34]  J. Hogg,et al.  Morphology of peripheral airways in current smokers and ex-smokers. , 2015, The American review of respiratory disease.

[35]  P. Paré,et al.  The structure and function of the pulmonary vasculature in mild chronic obstructive pulmonary disease. The effect of oxygen and exercise. , 1983, The American review of respiratory disease.