Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-beta1, vascular endothelial growth factor, and basic fibroblast growth factor in patients with chronic hepatitis C

AIM: To assess the role of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of fibrosis associated with chronic hepatitis C (CHC) and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results (complete response or no response). METHODS: Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed (Scheuer fibrosis score: 1-4 points). Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis (Scheuer fibrosis score: 0 points). Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin. RESULTS: TGF-beta1 levels were significantly higher in the study group compared to the control group (35.89 vs 32.37 ng/mL; P=0.023). Such differences were not found in VEGF and bFGF levels. In patients showing complete response (negative HCV RNA and normal ALT level), significant increase in VEGF (112.8 vs 315.03 pg/mL; P<0.05) and bFGF (2.51 vs 15.79 pg/mL; P=0.04) levels were found. Significant decrease in TGF-beta1 level was observed both in responders (37.44 vs 30.02 ng/mL; P=0.05), and in non-responders (38.22 vs 30.43 ng/mL; P=0.043). bFGF levels before the treatment were significantly lower (2.51 vs 5.94 pg/mL; P=0.04), and after the treatment significantly higher (15.79 vs 4.35 pg/mL; P=0.01) in patients with complete response than in those with no response. CONCLUSION: Among the analyzed parameters TGF-beta1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-beta1, VEGF, and bFGF levels. bFGF seems to have the highest usefulness in the prognosis of treatment efficacy.     

Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma

Purpose: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been suggested to be important mediators for tumor-induced angiogenesis. We measured serum VEGF and bFGF levels from patients with soft-tissue sarcomas and correlated serum VEGF and bFGF levels with tumor status at surgery and histological grading. Materials and methods: A group of 18 healthy controls and 85 patients with soft-tissue sarcoma were enrolled in this study. The patients were classified according to tumor status at surgery. Serum levels of VEGF and bFGF were also correlated with histological grading. VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Results: Serum VEGF and bFGF levels were significantly elevated in the patient group (VEGF: 580pg/ml, bFbF: 21pg/ml, P = 0.0001). The highest concentrations of serum VEGF and bFGF were found in patients with macroscopic tumor lesions or G3 histology. Serum VEGF levels showed a statistically significant correlation with tumor status and grading (P = 0.006 for tumor status, P = 0.0001 for grading). Conclusions: This study reveals that elevated preoperative serum VEGF and bFGF levels can be detected in the majority of patients with soft-tissue sarcoma. The significant correlation with tumor mass and histological grading suggests that a consecutive monitoring of VEGF and bFGF in the serum of patients with soft-tissue sarcoma might be a valuable marker for tumor follow-up. Received: 26 April 1999 / Accepted: 17 May 1999     

雾化吸入碱性成纤维细胞生长因子对血管性痴呆患者血管内皮生长因子的影响

目的:研究雾化吸入碱性成纤维细胞生长因子(b-FGF)对血管性痴呆患者血清血管内皮生长因子(VEGF)的影响。方法:采用临床痴呆评定量表(CDR)筛选出轻度血管性痴呆(VD)患者60例,分成轻度VD治疗组34例,轻度VD对照组26例,另设正常对照组30例,VD对照组患者常规抗动脉硬化、抗血小板聚集及抗痴呆治疗,VD治疗组在其对照组常规治疗基础上给予b FGF 4800 AU/d加入生理盐水10 m L氧气雾化吸入,每次10 min,1次/d,连续14 d。比较2组VD患者治疗前、治疗后14、30 d血清VEGF的表达。结果:2组VD患者治疗前血清VEGF水平明显低于正常对照组,VD治疗组患者治疗后14、30 d血清VEGF水平逐渐升高,与VD对照组比较有统计学意义(P0.01)。结论:b FGF通过鼻黏膜进入中枢神经系统,促进VD患者血清VEGF的表达。     

Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression

Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO(2) (pH 7.0, acidosis) or 5% CO(2) (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.     

非霍奇金淋巴瘤患者sVEGF和sbFGF水平的变化及临床意义

目的:研究非霍奇金淋巴瘤(NHL)患者血清血管内皮生长因子(sVEGF)及血清碱性成纤维细胞生长因子(sbFGF)水平与临床特征的关系,探索其临床意义.方法:ELISA法检测36例不同病期NHL患者sVEGF、sbFGF水平,并收集临床资料,进行统计分析.结果:NHL患者sVEGF、sbFGF水平明显高于对照组(均P＜...     

Elevated circulating levels of basic fibroblast growth factor and vascular endothelial growth factor in patients with acute myocardial infarction

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have both shown strong angiogenetic effects in ischemic animal models and it has been reported that these growth factors were increased after acute myocardial ischemia. However, there have been few reports on the serum levels of bFGF and VEGF after acute myocardial infarction (AMI), in particular there has not been a comparative study of bFGF and VEGF in human subjects. The time course of circulating levels of bFGF and VEGF was examined in 36 patients with AMI who were within 24h of the onset of the AMI. The serum bFGF and VEGF levels of 50 age- and sex-matched healthy volunteers served as the baseline value. All the patients had undergone coronary angiography on the day of admission (Day 0), but prior to that the serum bFGF and VEGF levels were examined by enzyme-linked immunoassay. The serum bFGF and VEGF levels were also evaluated on Days 7, 14 and 28. Creatine kinase, myosin light chain I and troponin-T were measured subsequently and radionuclide examinations were performed during the early phase of AMI to determine the infarct size. The serum bFGF levels were significantly increased at Day 0 and were maintained until Days 7 and 14. Although serum VEGF levels at Day 0 were similar to the baseline values, they showed a remarkable increase by Days 7 and 14. A high serum level of bFGF was detected in the acute phase of AMI, and a later increase in VEGF was determined in the sub-acute phase, which suggest that these 2 growth factors play an important role at different time points of the reconstructing process of infarcted myocardial tissue.     

Spider angiomas in patients with liver cirrhosis： Role of vascular endothelial growth factor and basic fibroblast growth factor

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated with spider angiomas in patients with liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122 +/- 13 vs. 71 +/- 11 pg/mL, P=0.003 for VEGF; 5.1 +/- 0.5 vs. 3.4 +/- 0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185 +/- 28 vs. 90 +/- 10 pg/mL, P=0.003 for VEGF; 6.8 +/- 1.0 vs. 4.1 +/- 0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95 % confidence interval [CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01, P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated in patients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.     

Cellular distribution of platelet-derived growth factor, transforming growth factor-beta, basic fibroblast growth factor, and their receptors in normal bone marrow

We performed an immunohistochemical study on 5 normal marrow samples and 3 fibrotic marrow samples to investigate the cellular distribution of various isoforms of platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their corresponding receptors. Immature hematopoietic precursors strongly expressed PDGF-B, all the TGF-beta isoforms, PDGFRbeta, TGFbetaRI and II, and FGFR1, 3, and 4. Megakaryocytes stained primarily for PDGF-B, TGF-beta2-3, and PDGFRbeta. Histiocytes displayed intense TGF-beta1, bFGF, and FGFR2 expression. Fibroblasts and endothelial cells carried receptors for all the aforementioned cytokines. The last 2 cell types also expressed the ligand cytokines to varied degrees.     

Marked elevation of vascular endothelial growth factor and basic fibroblast growth factor in pericardial fluid of patients with angina pectoris

Although we reported that basic fibroblast growth factor (bFGF) levels in pericardial fluid of patients with unstable angina are apparently increased, it was unclear whether vascular endothelial growth factor (VEGF) is also increased in patients with myocardial ischemia. Using an enzyme-linked immunosorbent assay, we measured the concentrations of VEGF and bFGF in pericardial fluid of 51 patients with open heart surgery. Patients were divided into group A (n=10) with class III unstable angina (Braunwald's classification), group B (n=24) with class I or II unstable angina or stable angina and group C (n=17) with non-ischemic heart disease. The VEGF level in pericardial fluid in group A was 83±7 pg/ml, being significantly (p<0.001) higher than the 27±3 pg/ml in group B and the 28±5 pg/ml in group C. The concentrations of bFGF in pericardial fluid in groups A and B were 1461±579 and 1224±161 pg/ml, respectively, significantly (p<0.05) higher than the 292±97 pg/ml in group C. The level of VEGF in pericardial fluid was increased only in patients with severe rest angina within 2 days before emergency coronary artery bypass graft surgery (CABG), while bFGF was increased in all patients undergoing CABG for coronary artery disease. Thus VEGF and bFGF may play important roles in mediating collateral growth in humans.     

Correlation of electroretinography b-wave absolute latency,plasma levels of human basic fibroblast growth factor,vascular endothelial growth factor,soluble fatty acid synthase,and adrenomedullin in diabetic retinopathy

BackgroundWe investigated the b-wave latency of electroretinogram (ERG), human basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), soluble fatty acid synthase (s-Fas), and adrenomedullin (ADM) in diabetic retinopathy.Patients and MethodsThirty control and 60 type II diabetic women (mean age 45±3.9 years, duration of diabetes 10.1±2.1 years) were investigated. Diabetics without complications (Group II) and with retinopathy (Group III) were diagnosed depending on clinical findings, abnormal fundus examination, and ERG. Plasma levels of b-FGF, VEGF, s-Fas, and ADM were measured.ResultsERG showed a significant increase of b-wave absolute latency, plasma b-FGF, VEGF, s-Fas, and ADM in diabetic retinopathy (P<.05). A positive correlation was found between b-wave latency and VEGF and s-Fas, and a negative correlation with b-FGF and ADM.ConclusionThis study elucidates the causative role of VEGF and s-Fas in diabetic retinopathy. VEGF may potently promote growth of endothelial cells and formation of new vessels implicated in proliferative retinopathy. s-Fas could be involved in advancement of apoptotic changes in retinopathy and high levels of b-FGF, and ADM may be compensatorily neuroprotective and vasculoprotective. The results showed that diabetic retinopathy is the result of multiple factors, so it is optimistic to believe that reversing VEGF or s-Fas will halt retinopathy, targeting multiple mechanisms simultaneously by administering combination treatments of VEGF antagonists; antiapoptotic drugs together with b-FGF and/or ADM may be prospective.     

Intracardiac basic fibroblast growth factor and transforming growth factor-beta 1 mRNA and their proteins expression level in patients with pressure or volume-overload right or left ventricular hypertrophy

OBJECTIVES: The aim of the study was to investigate the pathogenic role of intracardiac basic fibroblast growth factor (bFGF) and transforming growth factor beta-1 (TGF beta-1) mRNA and their protein expression level in patients with ventricular volume or pressure-overload. BACKGROUND: Myocardial hypertrophy is responsiveness of cardiomyocytes and interstitial cells to ventricular stress produced by ventricular preload or/and afterload and a series of growth factors. However, the molecular mechanism by which the changes of bFGF and TGF beta-1 mRNA and their protein expression level in patients with volume or pressure-overload lead to distinct forms of cardiac hypertrophy is unclear. METHODS: 32 patients were divided into two groups: 16 patients with cardiac volume overload leading to left ventricular hypertrophy (VG) and 16 patients with pressure overload leading to right ventricular hypertrophy (PG), respectively, as compared with 5 unexpected deaths of noncardiac disease (CG), which is determinated by echocardiography and/or pathologic examination following operation; intracardiac bFGF and TGF beta-1 mRNA and their protein expression level were determined by immunohistochemistry and in situ hybridization as well as image analysis; cardiomyocytes and fibril collagen of type I and III were examined by haemotoxylin and eosin (HE) staining or sirius-red staining. RESULTS: Cardiocyte transverse diameter and fibril collagen of extracellular matrix, intracardiac bFGF and TGF beta-1 mRNA and their protein expression level in patients with volume or pressure-overload were significantly increased in both VG and PG, as compared with CG. CONCLUSION: This is the first paper to suggest that intracardiac bFGF and TGF beta-1 play a pivotal role in patients with pressure or volume-overload leading to right or left ventricular hypertrophy, composed of cardiomyocyte hypertrophy and extracellular matrix proliferation.     

Serum levels of vascular endothelial growth factor and transforming growth factor-beta1 in patients with atrial fibrillation undergoing defibrillation therapy

We have previously reported that pulsatile mechanical stretch in vitro induced rapid secretion of vascular endothelial growth factor (VEGF) by cultured cardiac myocytes and that the stretch-induced secretion of VEGF was mainly mediated by secretion of transforming growth factor (TGF)-beta1 by cardiac myocytes in an autocrine fashion. To investigate whether tachycardia-induced mechanical overload increases serum levels of VEGF and TGF-beta1, we investigated the serum levels of VEGF and TGF-beta1 in patients with atrial fibrillation undergoing defibrillation therapy. The serum VEGF level before defibrillation was significantly increased in 13 out of 20 patients (89.48 +/- 16.09 pg/ml [mean +/- SE]). After defibrillation, the serum VEGF level in these 13 patients significantly (p = 0.019) decreased (65.04 +/- 16.61 pg/ml [mean +/- SE]), although it increased slightly in one patient. The serum TGF-beta1 level before defibrillation therapy (13.01 +/- 1.97 pg/ml [mean +/- SE]) in these 12 patients also decreased after defibrillation therapy (11.47 +/- 2.06 pg/ml [mean +/- SE]). The changes in serum VEGF level significantly correlated with those in the serum TGF-beta1 level in these 12 patients (r = 0.73, p < 0.05, n = 12). Our data suggest that tachyarrhythmia-induced mechanical overload can increase the serum VEGF level, which can be a useful clinical marker for relative myocardial oxygen shortage in such patients.     

Concentrations of hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor in pericardial fluid and plasma

Some angiogenic factors, including hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), have been reported to promote angiogenesis and improve myocardial perfusion in experimental models of ischemic heart disease. These factors are produced in various tissues, including myocardium. We measured the concentrations of HGF, bFGF, and VEGF by enzyme-linked immunosorbent assay in plasma and in pericardial fluid sampled during open heart surgery (12 patients with ischemic heart disease and 17 with nonischemic heart disease). HGF levels were significantly higher in plasma than in pericardial fluid (12.0 +/- 1.8 versus 0.26 +/- 0.04 ng/mL, P < 0.0001). On the other hand, bFGF levels were significantly higher in pericardial fluid than in plasma (243.5 +/- 50.9 versus 49.6 +/- 7.8 pg/mL, P = 0.009). VEGF levels were not significantly different between pericardial fluid and plasma (47.2 +/- 17.6 versus 24.5 +/- 3.6 pg/mL, P = 0.23). Concentrations of angiogenic factors in pericardial fluid and in plasma were not significantly different between patients with ischemic and nonischemic heart disease. These results suggest that the production, secretion, and kinetics of HGF, bFGF, and VEGF are different. These angiogenic factors may have different pathophysiologic roles.     

The role of vascular endothelial growth factor in angiogenesis and diabetic retinopathy

Diabetic retinopathy (DR), a DM microvascular complication, is the leading cause of blindness. Angiogenic factors such as vascular endothelial growth factor (VEGF) are involved in the pathogenesis of DR. VEGF-A is a potent, multifunctional cytokine that acts through the receptors VEGFR-1 and VEGFR-2 expressed in the vascular endothelium and causing increased vascular permeability and neovascularization stimulation in both physiological and pathological processes. The expression of VEGFR-1 is upregulated by hypoxia and is less responsive to VEGF compared to VEGFR-2 which is the main mediator mitogenic, angiogenic, and increased vascular permeability. VEGF polymorphisms have been studied in DR susceptibility and progression. Significant association between the polymorphism 634C / G and the presence of RD is reported mainly in relation to allele C. The homozygous CC is associated to proliferative RD and to increased vitreous and serum levels of VEGF suggesting that the presence of the C allele is an independent risk factor for RD. The knowledge of VEGF lead to the development of anti-VEGF drugs (pegaptanib, ranibizumab and bevacizumab) aiming to prevent pathological neovascularization. The anti-VEGF therapy is a reality in practice medical treatment of DR.