血管内皮生长因子与胸腔积液

血管内皮生长因子（VEGF）是目前已知活性最强、高度特异的血管生长因子。研究表明：VEGF可使血管通透性增加、渗出增多，在促进胸腔积液形成的过程中起重要作用。深入研究VEGF为进一步认识胸腔积液的发病机制及发展新的治疗策略提供了条件。     

Vascular endothelial growth factor in pleural effusions of different origin.

This study aimed to determine the diagnostic relevance of vascular endothelial growth factor (VEGF) in the pleural fluid and serum of patients with pleural effusions of different aetiology. VEGF was quantified in the pleural effusion fluid and serum of 96 patients with malignancies (58 lung cancers (CA) and 38 tumours with secondaries to the lung (TM)), 45 with congestive heart failure (CHF), 28 with tuberculosis (TB), 45 with acute infections (INF), and in the serum of 20 healthy controls. VEGF pleural effusion concentrations were significantly different in the main diagnostic groups. VEGF was higher in effusions of patients with malignancies (CA as well as TM) in comparison with INF, TB or CHF. In serum, however, high VEGF concentrations indicated CA, TM or INF, but not TB or CHF. Despite significant differences of VEGF levels in different patient groups, receiver-operating characteristic analysis revealed insufficient diagnostic value of VEGF for differential diagnosis of pleural effusions. In conclusion, vascular endothelial growth factor serum concentration is highly suggestive of the presence of lung disease in general, except for tuberculosis. In effusion fluid, the presence of vascular endothelial growth factor clearly indicates inflammatory or malignant origin. However, for diagnostic use, additional parameters besides vascular endothelial growth factor are mandatory.     

Vascular endothelial growth factor and proinflammatory cytokines in pleural effusions

To evaluate the predictive value of vascular endothelial growth factor (VEGF) in the differential diagnosis of pleuritis and its association with other proinflammatory cytokines in pleural effusion, we measured VEGF together with interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) in pleural effusions. We investigated 127 patients with pleural effusion (congestive heart failure: 21; parapneumonic: 27; tuberculous: 41; malignant: 38). We examined standard parameters of pleural effusion and measured pleural effusion VEGF, IL-1beta, TNF-alpha and sICAM-1 using enzyme-linked immunosorbent assay. VEGF level was significantly higher in malignant effusion than in other groups. TNF-alpha level was significantly higher in tuberculous pleurisy than in other groups. In tuberculous pleurisy VEGF level showed significant positive correlations with mononuclear cell counts and all investigated cytokines. The sensitivity and specificity of VEGF in the diagnosis of malignancy was 100 and 84%, respectively (cutoff = 2000 pg/ml). The sensitivity and specificity of VEGF and TNF-alpha in the diagnosis of tuberculous pleurisy (VEGF titer <2000 pg/ml and TNF-alpha titer > 55 pg/ml) was 88.9 and 77.1%, respectively. We propose that measurement of VEGF together with TNF-alpha is helpful in differentiating between tuberculous pleurisy and malignant pleural effusion and that VEGF correlates with proinflammatory cytokines especially in tuberculous pleurisy. We also propose that measurement of pleural VEGF is helpful for the diagnosis of malignant pleural effusion.     

Vascular endothelial growth factor: the key mediator in pleural effusion formation

Pleural effusion is common in clinical practice. Increased vascular permeability and leakage play a principal role in the development of exudative pleural effusions. In vitro and in vivo evidence have solidly established vascular endothelial growth factor (VEGF), a potent inducer of vascular permeability, as a crucial mediator in pleural fluid formation. VEGF is present in high quantities in human effusions. In the pleural space, mesothelial cells, infiltrating inflammatory cells, and (in malignant pleuritis) cancer cells contribute to the VEGF accumulation in the pleural fluids. Pleural fluid VEGF is biologically active and may promote tumor growth and chemotaxis. Strategies to antagonize the VEGF activity at various target points of its signaling pathway have shown success in vitro and in animal models of malignant pleural or peritoneal effusions. Novel agents targeting VEGF activities are undergoing clinical trials. Regulation of VEGF activity and vascular permeability represent a rapidly expanding field of research, which is likely to provide further insight in the pathophysiology of pleural fluid formation.     

Vascular endothelial growth factor

An understanding of the mechanisms regulating growth and differentiation of vascular endothelial cells is very important for cardiovascular biology and medicine. Several potential regulators of angiogenesis have been identified, including acidic and basic fibroblast growth factors, epidermal growth factor, platelet-derived endothelial cell growth factor, transforming growth factors and β, and tumor necrosis factor (TNF-). Vascular endothelial growth factor (VEGF) is unique among these agents by virtue of its direct and specific mitogenic effects on endothelial cells combined with the fact that it is a secreted polypeptide. By alternative splicing of mRNA, VEGF may exist in four different isoforms that have similar biologic activities but differ markedly in their secretion pattern. VEGF is emerging as an important regulator of developmental and ovarian angiogenesis. Its action is purely paracrine as it is produced by a variety of cell types, but its receptors are only in endothelial cells. There is no evidence that endothelial cells in vivo produce VEGF. The VEGF mRNA is expressed at high level by a variety of human tumors, suggesting that VEGF may be a tumor angiogenesis factor. This hypothesis is supported by the finding that monoclonal antibodies specific for VEGF are able to suppress tumor growth in vivo. Therefore, VEGF antagonists may be used for the treatment of malignancies and, possibly, other angiogenic diseases. The VEGF protein has therapeutic potential as an inducer of neovascularization in conditions characterized by impaired tissue perfusion like obstructive atherosclerosis.     

Vascular endothelial growth factor levels in post-CABG pleural effusions are associated with pleural inflammation and permeability

BACKGROUND: Vascular endothelial growth factor (VEGF) participates in the pathogenesis of exudative pleural effusions (PEs). In the present study, we determined the pleural fluid (PF) and serum VEGF levels in patients with post-coronary artery by-pass grafting (post-CABG) PEs. METHODS: Thirty-eight patients with post-CABG (two with bilateral) PEs were studied. PEs were divided into "early" (occurring earlier than 30 days after surgery) and "late" ones. VEGF levels were measured using ELISA. RESULTS: (i) Serum and PF VEGF levels did not differ significantly when all the patients (P=0.053) or those with late effusions (P=0.6) were analyzed; serum VEGF levels were significantly elevated in comparison to PF VEGF levels in patients with early (P=0.007) effusions. (ii) Serum VEGF levels were significantly higher in patients with early than in those with late effusions (P=0.033), while PF VEGF levels were not significantly different between the two groups (P=0.77). (iii) PF VEGF levels were higher than corresponding serum levels in 4/24 patients with early and in 10/16 patients with late post-CABG PEs (P=0.006). (iv) In PEs VEGF levels significantly correlated with red blood cells (P=0.015), nucleated cells (P=0.003), protein levels (P=0.002) and lactate dehydrogenase (LDH) levels (P=0.04). CONCLUSION: In post-CABG PEs, preferential local production of VEGF in the pleural cavity is most commonly observed a month or later after surgery. The fact that in PEs VEGF levels correlate with markers of pleural inflammation (inflammatory cells and LDH levels) and vascular hyperpermeability (protein levels) suggests that VEGF may be involved in the pathogenesis of post-CABG PEs.     

Vascular endothelial growth factor correlates with matrix metalloproteinase-9 in the pleural effusion

Vascular endothelial growth factor (VEGF) is a potent, multifunctional cytokine that contributes to angiogenesis and inflammation. Matrix metalloproteinase-9 (MMP-9) is one of the major proteolytic enzymes that degrade various components of the extracellular matrix. Few data are available on the potential relationship between VEGF and MMP-9 in the accumulation of pleural effusion. We examined levels of VEGF and MMP-9 by means of enzyme immunoassay, zymographic analysis, and Western blot analysis in the patients with liver cirrhosis, tuberculosis, or lung cancer. The levels of VEGF and MMP-9 were significantly increased in the pleural fluids and sera of patients with tuberculosis and were even higher in patients with lung cancer compared with the patients with liver cirrhosis. A significant correlation was established between the level of VEGF and the level of MMP-9 in the pleural effusion. These results suggest that overproduction of VEGF and MMP-9 is associated with accumulation of the pleural effusion in tuberculosis and lung cancer. The relationship between VEGF and MMP-9 in the pleural effusion may have a role in the pathogenesis of pleural fluid formation.     

Vascular endothelial growth factor level correlates with transforming growth factor-beta isoform levels in pleural effusions

BACKGROUND: Recent studies have demonstrated high levels of vascular endothelial growth factor (VEGF) in exudative pleural effusions and a possible etiologic role. The factors regulating VEGF accumulation in the pleural space are unknown. Transforming growth factor (TGF)-beta is a potent stimulator of VEGF expression in vitro. We hypothesized that TGF-beta induces VEGF production in pleural tissues, and, hence, the pleural fluid VEGF levels should correlate with the levels of TGF-beta in pleural fluid of different etiologies. METHODS: Seventy pleural fluid samples were analyzed. These included 20 malignant, 13 post-coronary artery bypass grafting (CABG), 8 parapneumonic, 11 miscellaneous exudative, and 18 congestive heart failure (CHF) pleural effusions. RESULTS: Pleural fluid VEGF levels showed good correlation with those of TGF-beta(1) (r = 0.58; p < 0. 0001), TGF-beta(2) (r = 0.43; p < 0.001), and lactate dehydrogenase (r = 0.65; p < 0.001). The levels of TGF-beta(1) and TGF-beta(2) also were correlated (r = 0.60; p < 0.0001). The median levels of TGF-beta(1) (2,480 pg/mL) and TGF-beta(2) (266 pg/mL) in the CHF group were significantly lower than those in the malignant (TGF-beta(1), 4,902 pg/mL; TGF-beta(2), 428 pg/mL), post-CABG (TGF-beta(1), 5,456 pg/mL; TGF-beta(2), 377 pg/mL), parapneumonic (TGF-beta(1), 5,024 pg/mL; TGF-beta(2), 464 pg/mL), and miscellaneous exudate groups (TGF-beta(1), 7,690 pg/mL; TGF-beta(2), 369 pg/mL). There was no significant difference in TGF-beta(1) and TGF-beta(2) levels among the four exudate groups. CONCLUSIONS: VEGF levels in pleural effusions are significantly correlated with the levels of TGF-beta(1) and beta(2) isoforms. VEGF, TGF-beta(1), and TGF-beta(2) levels were all higher in exudative effusions than in effusions secondary to CHF.     

Vascular endothelial growth factor in Henoch-Schonlein purpura.

OBJECTIVE: To investigate the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of Henoch-Schonlein purpura (IHSP). METHODS: Plasma VEGF levels were determined in 22 children by ELISA. Ten age matched healthy children served as controls. VEGF expression was evaluated by immunohistochemistry within the cutaneous vasculitic lesion as well as the nonaffected skin and in the skin specimens during the resolution of the disease. RESULTS. Plasma VEGF levels in pg/ml (mean +/- SE) were significantly higher during the acute phase (407.8 +/- 64.92) when compared with the levels seen during the resolution phase (202.17 +/- 26.6; p < 0.002) and in healthy controls (135 +/- 22.8; p < 0.001). Analysis showed that there was a correlation with erythrocyte sedimentation rate. C-reactive protein, white blood cell and platelet count. In all skin specimens, the intensity of the staining of VEGF in the epidermis, dermis, and vascular endothelial bed were evaluated and scored from (+) to (++++). VEGF expression in the epidermis and the vascular bed was more intense in resolving lesions compared with acute vasculitic lesions (p < 0.05). CONCLUSION: Our results suggest that as a potent permeability, chemotactic, and migratory factor, VEGF may play a crucial role in the morphological and functional changes of the vascular bed and inflammatory reaction in HSP.     

Vascular endothelial growth factor B, a novel growth factor for endothelial cells.

We have isolated and characterized a novel growth factor for endothelial cells, vascular endothelial growth factor B (VEGF-B), with structural similarities to vascular endothelial growth factor (VEGF) and placenta growth factor. VEGF-B was particularly abundant in heart and skeletal muscle and was coexpressed with VEGF in these and other tissues. VEGF-B formed cell-surface-associated disulfide-linked homodimers and heterodimerized with VEGF when coexpressed. Conditioned medium from transfected 293EBNA cells expressing VEGF-B stimulated DNA synthesis in endothelial cells. Our results suggest that VEGF-B has a role in angiogenesis and endothelial cell growth, particularly in muscle.     

Vascular endothelial growth factor and microvascular permeability.

Vascular Endothelial Growth Factors (VEGFs) are endogenously produced vascular cytokines which result in angiogenesis, vasodilatation, and increased microvascular permeability in vivo. They are endothelial specific and result in mitosis, migration, stress fiber formation and increased permeability of endothelial cells in culture. They have been critically implicated in a host of pathological conditions including solid tumor growth and diabetes, and been proposed as a therapy for coronary and peripheral ischemic disease. However, the potent permeability-enhancing properties of VEGFs are very poorly understood. The pharmacology, signal transduction pathways, intracellular signaling mechanisms, and ultrastructural changes which result in increased permeability are still not clear. This review discusses the available evidence for how VEGFs increase permeability in vivo, and some of the pitfalls in interpreting experiments which do not take into account the vasoactive properties of VEGFs. It also discusses the clinical implications of the permeability enhancing effect of VEGFs, and the relevance of these studies to development of new therapies.     

Vascular endothelial growth factor in colorectal cancer

Background Angiogenesis plays an important role in colorectal cancer progression. Evidence from preclinical and clinical studies indicates that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in human colorectal cancer and is associated with formation of metastases and poor prognosis. Based on these results it was hypothesized that attacking one or more of the VEGF-mediated mechanisms may be promising in the treatment of colorectal cancer.Aims This article reviews the role of VEGF in colon cancer and summarizes recent advances in the treatment of colorectal cancer by anti-VEGF strategies.M. Guba and H. Seeliger contributed equally to this paper     

Vascular endothelial growth factor levels in the serum and synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: To determine the vascular endothelial growth factor (VEGF) concentrations in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and to search for relationships between VEGF levels and clinical and laboratory variables. METHODS: We measured VEGF levels using an enzyme-linked immunosorbent assay. Serum samples were obtained from 99 RA patients, 49 osteoarthritis (OA) patients, and 80 normal controls. Paired samples of serum and SF were collected from 32 patients with RA and 15 with OA. RESULTS: The mean serum VEGF concentration was 590.1 pg/ml for RA patients, 286.7 pg/ml for OA patients, and 265.8 pg/ml in controls. The serum VEGF concentration was significantly higher in the RA patients than in the OA patients or the controls (both p < 0.001). Furthermore, the VEGF levels in SF from RA patients were significantly higher than in SF from OA patients (p = 0.017). However, there was no correlation between VEGF levels in serum and SF from the same RA patients. The serum VEGF concentration was correlated with the ESR, serum CRP concentration, serum rheumatoid factor, number of tender and swollen joints, Modified Health Assessment Questionnaire, and patient and physician global assessments of disease activity in RA patients. CONCLUSION: These results suggest that VEGF level is related to RA disease activity, suggesting that VEGF may play some role in the pathogenesis of RA.     

Vascular endothelial growth factor production in polymyalgia rheumatica

OBJECTIVE: To evaluate peripheral production and synovial expression of vascular endothelial growth factor (VEGF) in polymyalgia rheumatica (PMR). METHODS: Circulating levels of VEGF in PMR (serum concentration and in vitro release by peripheral blood mononuclear cells [PBMC]) were investigated by enzyme-linked immunosorbent assay. Local expression of VEGF in shoulder synovial tissue was investigated by immunohistochemical analysis. Investigations were performed in patients with active, untreated disease and in patients treated with corticosteroids. RESULTS: VEGF serum concentrations were significantly higher in untreated PMR patients than in normal control subjects. During steroid treatment, VEGF serum concentrations reached their lowest level after the sixth month of treatment. PBMC isolated from untreated PMR patients spontaneously secreted a higher amount of VEGF compared with PBMC from control subjects. Corticosteroid therapy did not affect the ability of PBMC to produce VEGF. Immunohistochemical staining performed on shoulder synovial tissue showed VEGF expression in both the lining layer and the sublining area. In 3 of 4 treated patients, no VEGF staining was found in synovial tissue during corticosteroid therapy. VEGF expression correlated with vessel density, but was not associated with alphavbeta3 and alphavbeta5 integrin expression. CONCLUSION: Peripheral and local VEGF releases have different responses to steroid treatment in PMR. The lack of response to corticosteroids by peripheral VEGF production supports the hypothesis that systemic involvement is dominant in PMR. At the synovial level, VEGF production is linked to vascular proliferation and is thus directly involved in the pathogenesis of synovitis.     

血管内皮生长因子与支气管哮喘

血管内皮生长因子(VEGF),又称血管渗透因子(VPF),是一种广泛存在于机体组织的细胞因子,参与体内多种疾病过程,本文就VEGF的生物学特性及其与支气管哮喘的关系进行综述。