Vascular endothelial growth factor in human lung transplantation

STUDY OBJECTIVES: To determine levels of the vascular endothelial growth factor (VEGF) isoform consisting of 165 amino acids (VEGF(165)) in BAL fluid (BALF) from lung transplant recipients (LTXs). DESIGN: Bronchoscopy with BAL was performed on LTXs and normal volunteers (NVs). SETTING: University hospital. PARTICIPANTS: LTXs (n = 57) and NVs (n = 15). MEASUREMENTS AND RESULT: VEGF(165) concentrations in BALF were higher (mean +/- SEM, 240 +/- 32 pg/mL) for NVs (n = 15) vs 133 +/- 14 pg/mL for LTXs (n = 37) who were stable without evidence of significant rejection or infection at 6 months after transplantation (p < 0.0001). BALF VEGF concentrations sampled at 24 to 48 h, 2 weeks, 4 weeks, and 6 months after transplantation for 11 LTXs who lacked rejection or infection at any time point were 71 +/- 8 pg/mL, 80 +/- 20 pg/mL, 82 +/- 13 pg/mL, and 167 +/- 31 pg/mL, respectively. VEGF concentrations in BALF for LTXs with cytomegalovirus (CMV) pneumonia were 55 +/- 12 pg/mL (n = 10), 117 +/- 33 pg/mL for grade A3 acute rejection (n = 9), and 82 +/- 17 pg/mL (n = 14) for active bronchiolitis obliterans syndrome (BOS). Concentrations of VEGF in BALF at 6 months for the 32 stable recipients with bilateral lung transplantation were significantly higher for those with higher values for FEV(1), and BALF VEGF concentrations were significantly lower in BALF at 6 months for those recipients who subsequently went on to develop BOS (86 +/- 19 pg/mL) vs those who did not (158 +/- 18 pg/mL; p = 0.03). Serum concentrations of VEGF did not correlate with VEGF concentrations in BALF, but serum VEGF was 291 +/- 62 pg/mL at 10 to 14 days after transplantation vs 130 +/- 20 pg/mL at 4 weeks for nine LTXs with paired samples (p < 0.02). Serum VEGF concentrations for NVs (n = 15) were 102 +/- 15 pg/mL vs 94 +/- 17 for stable LTXs (n = 12) at 24 weeks after transplantation and 123 +/- 33 pg/mL for LTXs with active BOS (n = 10). CONCLUSIONS: BALF VEGF concentrations are particularly depressed at early time points following lung transplantation, gradually improve in the absence of significant rejection or infection, and are lower with active rejection or CMV pneumonia.     

The evaluation to relationship between serum vascular endothelial growth factor (VEGF) level, metastases and other tumor markers in patients with lung cancer

Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis. Increased expression of VEGF may be associated with advanced stage and poor prognosis in patients with lung cancer. We investigated the relationship between serum VEGF level and lung cancer stage. We also studied the correlation between serum VEGF level and some other tumor markers. Forty newly diagnosed lung cancer (31 non-small cell, 9 small cell) patients and 25 age-matched controls were enrolled in this study. Serum VEGF levels of lung cancer group (345.16 +/- 159.36 pg/mL) were significantly higher than that of the control group (230.36 +/- 47.87 pg/mL) (p< 0.001). The area under the ROC curve was 0.727 (p< 0.05) for serum VEGF threshold of 249.8 pg/mL predictive sensitivity and specificity, for lung cancer were respectively 70.0% and 76.0%. There were no significant relationship between serum VEGF level and age, gender, histologic type, lung cancer stage, distant metastases and site of metastases. In addition, there were no correlation between serum VEGF level and other tumor markers (NSE, CYFRA 21-1, CEA, CA125, LDH).     

Clinical significance of vascular endothelial growth factor in patients with primary lung cancer

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an angiogenesis factor closely associated with the growth and metastasis of malignant tumours. METHODOLOGY: In the present study, we measured plasma VEGF levels in 20 normal subjects (N), 35 patients with benign lung diseases (B), 28 patients with untreated advanced lung cancer (NT) and 10 patients with treated lung cancer (T). In addition, we measured the VEGF levels in pleural effusions from five patients with primary lung cancer and two patients with active infectious diseases. Vascular endothelial growth factor was measured by ELISA. RESULTS: The mean (+/-SD) plasma VEGF level in NT patients (160.8 +/- 177.4 pg/mL) was fivefold higher than that in other patient groups (T, 17.7 +/- 4.9 pg/mL; B, 28.3 +/- 17.6 pg/mL) and the N group (14.9 +/- 7.0 pg/mL; P < 0.01). Vascular endothelial growth factor from lung cancer pleural effusions (17 526.0 +/- 22 498.2 pg/mL) was 25-fold higher than that from patients with active infectious diseases (665.5 +/- 259.0 pg/mL). CONCLUSIONS: Plasma VEGF may be a good clinical indicator for the assessment of primary lung cancer and pleural effusion VEGF in primary lung cancer is higher than pleural effusion VEGF in patients with inflammatory diseases.     

血管生成素-1对小鼠早期急性肺损伤的保护作用

目的 观察血管生成素-1(Ang-1)对油酸致小鼠早期急性肺损伤的保护作用,探讨Ang-1对小鼠早期急性肺损伤血管内皮细胞生长因子(VEGF)表达的影响.方法 96只BALB/c雌性小鼠按随机数字表法分为4组,每组24只.正常对照组:尾静脉注射生理盐水(0.9 ml/kg);急性肺损伤组:尾静脉注射油酸(0.9 ml/kg)制备急性肺损伤模型;正常对照+Ang-1组:注入生理盐水4 h后腹腔内注射Ang-1(312.5μg/kg);急性肺损伤+Ang-1组:注入油酸4 h后腹腔内注射Ang-1(312.5μg/kg);8 h后各组随机抽12只小鼠处死后行支气管肺泡灌洗(BAL),另外12只小鼠右肺称重后烘干,左肺留取病理标本;分别测定肺湿/干重比、支气管肺泡灌洗液(BALF)中细胞总数、中性粒细胞数及蛋白含量变化;采用酶联免疫吸附(ELISA)法测定血清和BALF中自细胞介素-6(IL-6)、VEGF含量;光镜观察并盲法评分比较肺组织病理学改变;采用免疫组化法检测肺组织中VEGF的表达.采用SPSS 10.0软件.数据以-x±s表示,多组间比较采用单因素方差分析,组间比较采用LSD-t检验,P＜0.05为差异有统计学意义.结果 急性肺损伤+Ang-1组肺湿/干重比、BALF中蛋白含量和细胞总数、中性粒细胞、血清和BALF中IL-6含量、血清VEGF含量分别为4.09±0.14、(176±13)μg/ml、(34.4±4.1)×104/L、(19.85±3.93)×103/L、(1318±62)pg/ml、(652±17)pg/ml、(48±5)pg/ml,与急性肺损伤组[5.32±0.51、(227±12)μg/ml、(42.2±5.2)×104/L、(26.22±2.22)×103/L、(1510±117)pg/ml、(744±13)pg/m1、(74±5)pg/ml]比较差异有统计学意义(t值分别为8.16、9.92、4.02、4.88、5.03、19.18、14.81,P均＜0.01);而急性肺损伤+Ang-1组BALF中VEGF含量[(179±15)pg/ml]与B组[(140±20)pg/ml]比较差异有统计学意义(t=5.31,P＜0.01);急性肺损伤+Ang-1组肺损伤评分为(1.84±0.12)分,急性肺损伤组为(3.44±0.21)分,两组比较差异有统计学意义(t=24.16,P＜0.01).肺组织中VEGF表达吸光度(A)值急性肺损伤+Ang-1组为549±72,与急性肺损伤组(342±85)比较差异有统计学意义(t=5.22,P＜0.01);急性肺损伤+Ang-1组与正常对照组(768±111)比较差异亦有统计学意义(t=5.35,P＜0.01);正常对照+Ang-1组和正常对照组肺组织中VEGF吸光度(A)值表达比较差异无统计学意义(t=0.69,P＞0.05).结论 Ang-1对油酸致小鼠早期急性肺损伤可减轻渗出、抑制炎性细胞浸润和炎症因子动员,同时Ang-1可引起小鼠早期急性肺损伤血清VEGF表达降低,而BALF和肺组织中VEGF表达增加.提示Ang-1对油酸致小鼠早期急性肺损伤有一定的保护作用.     

Elevated vascular endothelial growth factor in systemic sclerosis

OBJECTIVE: To determine the serum levels of vascular endothelial growth factor (VEGF) in patients with systemic sclerosis (SSc) and to search for relationships between its serum levels and the clinical manifestations. METHODS: Serum levels of VEGF in patients with SSc and healthy controls were determined by ELISA. At the time of blood sampling, individual organ involvement was assessed, and a video microscope and PC based image processing were used to visualize nailfold capillaries and to quantify capillary density. RESULTS: Serum levels of VEGF in 48 patients with SSc were significantly higher than in 30 controls (432 +/- 356 vs 91 +/- 64 pg/ml; p < 0.001). Patients with diffuse cutaneous SSc (n = 21) had higher levels of serum VEGF than those with limited cutaneous SSc (n = 27) (432 +/- 356 vs 135 +/- 127 pg/ml; p < 0.001). Serum VEGF levels correlated well with the extent of skin sclerosis, as determined by modified Rodnan skin score (r = 0.656, p < 0.001) and serum TGF-beta levels (r = 0.530, p < 0.001). In particular, serum VEGF levels were inversely correlated with the capillary density of nailfold (r = -0.649, p < 0.001). However, no significant differences were found in the serum levels of VEGF between patients with systemic organ involvement and those without. CONCLUSION: The extent of skin sclerosis may contribute to the elevation of serum VEGF and high VEGF levels may serve as a surrogate indicator of capillary damage in SSc.     

Vascular endothelial growth factor in malignant and benign pericardial effusion

Background:

The pathogenetic role of vascular endothelial growth factor (VEGF) in malignant pericardial effusion and diagnostic value of pericardial VEGF levels to discriminate malignant from benign pericardial effusions are uncertain.

Hypothesis:

We hypothesized that pericardial VEGF levels would be higher in malignant than benign pericardial effusion and that VEGF would be a useful marker for the diagnosis of malignant pericardial effusion.

Methods:

Using an enzyme‐linked immunosorbent assay, we assessed pericardial and serum VEGF levels in patients with malignant pericardial effusion (n = 19), in patients with nonmalignant pericardial effusion (n = 30), and for control, in patients without pericardial disease (n = 26).

Results:

Vascular endothelial growth factor pericardial levels in malignant pericardial effusion (13 593.8 ± 22 410.24 pg/mL) were significantly higher compared with VEGF in nonmalignant effusion (610.63 ± 1289.08 pg/mL; P = 0.001) and pericardial fluid (5.5 ± 15.97 pg/mL; P < 0.001). In serum, VEGF was significantly higher in patients with nonmalignant pericardial effusion (188.3 ± 240.35 pg/mL) compared with patients with malignant pericardial effusion (67.52 ± 125.77 pg/mL; P = 0.024) and coronary artery disease patients (29.13 ± 76.26 pg/mL; P < 0.001). Pericardial VEGF levels were significantly higher than matched serum levels only in patients with malignant pericardial effusion (P = 0.023). Pericardial VEGF levels ≥2385 pg/mL had 75% sensitivity and 90% specificity for the recognition of malignant pericardial effusion in patients with breast or lung cancer.

Conclusions:

Vascular endothelial growth factor levels in pericardial effusion are markedly elevated in patients with malignant pericardial effusion, indicating abundant local release within the pericardial cavity. It is thus possible that VEGF participates in the pathogenesis of malignant pericardial effusion. Measurement of VEGF in pericardial effusion offers potential as a diagnostic tool to discriminate malignant from benign effusions in patients with breast or lung cancer. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients

STUDY OBJECTIVE: To investigate the prognostic significance of interleukin (IL)-10 serum levels in advanced non-small cell lung cancer (NSCLC) patients. DESIGN: IL-10 serum levels were measured before chemotherapy, on completion of therapy, and at follow-up by means of a commercially available enzyme-linked immunoassay. The results were then analyzed in comparison with other prognostic variables, and a model predicting overall survival (OS) and time to treatment failure (TTF) was finally generated. SETTING: University hospital. PATIENTS: Sixty consecutive patients with TNM stage III or IV NSCLC undergoing conventional platinum-based regimens. RESULTS: Elevated levels of serum IL-10 were found in cancer patients with respect to healthy control subjects (17.7 +/- 4.4 vs 9.2 +/- 1.5 pg/mL, respectively; p < 0.05), with patients with metastatic disease showing significantly higher levels than patients with undisseminated cancer (21.0 +/- 4.2 vs 14.3 +/- 1.2 pg/mL, respectively; p < 0.05). Following completion of treatment, patients were classified as responders if they had achieved either one of the following: complete response, partial response, or stable disease; and nonresponders, in case of progressive disease. Retrospective analysis of basal IL-10 serum levels in these two subgroups showed a significant difference between responders and nonresponders (15.2 +/- 2.2 vs 21.4 +/- 4.2 pg/mL, respectively; p < 0.05). Moreover, a further significant increase in IL-10 serum levels was observed in nonresponders at the end of therapy (21.4 +/- 4.2 vs 26.0 +/- 4.3 pg/mL, prechemotherapy and postchemotherapy, respectively; p < 0.05), whereas values in responders were found to have significantly decreased (15.2 +/- 2.2 vs 14.8 +/- 2.2 pg/mL, prechemotherapy and postchemotherapy, respectively; p < 0.05). Using univariate and multivariate analyses, both OS and TTF were shown to be affected by the mean pathologic levels of IL-10. Stepwise regression analysis identified IL-10 serum level and stage as the prognostic factors related to OS, and IL-10 serum level and performance status as the prognostic factors related to TTF. CONCLUSIONS: In conclusion, this study shows that the measurement of pretreatment IL-10 serum levels is of independent prognostic utility in patients with NSCLC and may be useful for detection of disease progression.     

Serum vascular endothelial growth factor levels are elevated in metastatic differentiated thyroid cancer but not increased by short-term TSH stimulation

Solid tumor formation requires the development of a blood supply adequate to meet the metabolic demands of the enlarging tumor mass that cannot be sustained by simple diffusion. One principal stimulant to endothelial cell growth and migration, vascular endothelial growth factor (VEGF), is synthesized and secreted by thyroid cancer cells. Furthermore, VEGF overexpression is associated with an aggressive thyroid cancer phenotype in both animal models and clinical-pathological studies. In other malignancies, elevated serum levels of VEGF often correlate with stage of disease and other poor prognostic clinical features. Therefore, we hypothesized that serum VEGF levels would be significantly higher in patients with persistent or recurrent thyroid cancer than in those cured of the disease. Because TSH stimulates both normal and neoplastic thyroid cells, we also proposed that serum VEGF would be further increased by TSH stimulation. Sixty-nine patients with either papillary or follicular thyroid cancer, status post total thyroidectomy, and prior radioactive iodine ablation, who had undergone routine recombinant human TSH (rhTSH, Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) assisted whole-body radioactive iodine scanning, were included in this study. This cohort (mean age 53 +/- 16 yr, 51% female) included 21 patients with no evidence of disease and 48 patients with local or distant metastases. Stored serum samples obtained for standard Tg determinations before and 72 h following standard rhTSH stimulation were identified and assayed for VEGF 165 (R \[amp ]\ D Systems, Minneapolis, MN). Baseline serum VEGF levels obtained at a time of TSH suppression were significantly higher in patients with known metastatic disease than in those with no evidence of disease (416 +/- 62 pg/ml vs. 185 +/- 25 pg/ml, P = 0.001). Patients with distant metastases had baseline serum VEGF levels that did not differ significantly from patients with only cervical recurrences (455 +/- 90 pg/ml in distant metastases vs. 330 +/- 44 pg/ml for local cervical recurrences). Short-term TSH stimulation, although causing a significant rise in serum Tg, resulted in no significant increase in serum VEGF measured 72 h after rhTSH injection in either the patients with known metastatic disease (416 +/- 62 pg/ml baseline vs. 419 +/- 71 pg/ml after TSH stimulation) or in cured patients (185 +/- 25 pg/ml baseline vs. 191 +/- 33 pg/ml after TSH stimulation). Subgroup analysis revealed that patients with metastatic disease arising from well differentiated primary thyroid cancers had significantly higher serum VEGF levels than patients with metastatic disease arising from poorly differentiated thyroid cancer primaries (485 +/- 74 pg/ml vs. 167 +/- 32 pg/ml, P = 0.003 by ANOVA). Poorly differentiated metastatic thyroid cancers had serum VEGF levels indistinguishable from patients cured of disease (167 +/- 32 pg/ml vs. 186 +/- 25 pg/ml). In summary, serum VEGF is significantly elevated in patients with metastatic differentiated thyroid cancer but not in those with poorly differentiated thyroid cancer metastases. No measurable increase in serum VEGF levels can be detected 72 h after short-term TSH stimulation with rhTSH. We conclude that serum VEGF may serve as a clinical useful marker of residual differentiated thyroid cancer.     

Serum hepatocyte growth factor and interleukin-6 levels can distinguish patients with primary or metastatic liver tumors from those with benign liver lesions

Hepatocyte growth factor (HGF) is a potent stimulator of angiogenesis and cancer metastasis. Interleukin-6 (IL-6) is a pleiotropic cytokine that can act as an autocrine or paracrine growth factor in various tumor cells. In this study, we investigated the role of serum HGF and IL-6 levels to distinguish primary or metastatic liver tumors from benign liver lesions. Serum HGF and IL-6 levels were measured in 64 cancer patients and 12 healthy controls. Patients were divided into 5 groups: Group-1 (n=24): Breast cancer patients in complete remission without any liver lesion, Group-2 (n=8): Breast cancer patients in complete remission with benign liver lesion, Group-3 (n=10): Breast cancer patients with liver metastasis, Group-4 (n=11): Metastatic breast cancer patients without liver metastasis, Group-5 (n=11): Patients with hepatocellular carcinoma. Group-6 (n=12): Healthy controls. Serum HGF levels were found to be higher in group-5 (606.4+/-255.8 pg/ml) than those in group-1 (*305.6+/-42.3 pg/ml), group-2 (*293.9+/-44.8 pg/ml), group-4 (**358.4+/-81.9 pg/ml) and group-6 (*305.8+/-24.9 pg/ml) (*p<0.001, **p<0.05). Patients in group-3 (448.9+/-157.3 pg/ml) had higher serum HGF levels than those in group-1, group-2 and group-6 (p<0.05). Serum IL-6 levels were found to be higher in group-5 (54.9+/-37.4 pg/ml) than those in group-1 (9.7+/-6.4 pg/ml), group-2 (9.5+/-4.8 pg/ml), group-4 (17.6+/-19.6 pg/ml) and group-6 (12.6+/-5.2 pg/ml, p<0.05). Patients in group-3 (32.5+/-36.9 pg/ml) had higher serum IL-6 levels than those in group-1, 2 and group-6, but these were not statistically significant (p>0.05). This study showed that primer and metastatic liver tumors had higher serum HGF and IL-6 levels than other patients and controls. Measurements of these markers in serum may be used to distinguish patients with primer liver tumors or breast cancer patients with liver metastasis from those with benign liver lesions or non-metastatic patients.     

Serum levels of vascular endothelial growth factor dependent on the stage progression of lung cancer

STUDY OBJECTIVE: In lung cancer, vascular endothelial growth factor (VEGF) is an important cytokine and is correlated with tumor vessel density, malignant pleural effusions, and coagulation-fibrinolysis factors in vitro. We investigated the correlation between serum VEGF level and stage progression in lung cancer to study the predicted value of VEGF level. We also studied whether coagulation-fibrinolysis factors and PaO(2) levels, which are also important factors for the prediction of the clinical course, are correlated with VEGF. METHODS: Forty-nine patients with lung cancer were investigated prospectively. VEGF levels of sera and malignant effusions, and plasma concentrations of coagulation-fibrinolysis factors were measured by enzyme-linked immunosorbent assay. We measured PaO(2) levels in all patients at rest. RESULTS: Serum levels of VEGF were increased significantly according to stage progression. Additionally, plasma concentrations of D dimer, thrombin-antithrombin complex (TAT), and tissue plasminogen activator/plasminogen activator inhibitor type I complex were elevated significantly according to stage progression. The serum VEGF level had a significant positive correlation with the TAT and D dimer levels. Serum VEGF levels had a significant negative correlation with PaO(2) levels. The incidence of cerebral vascular disorder was significantly higher in the patients with systemic hypoxemia than in those without (p<0.05). Mean VEGF levels in malignant effusions in eight patients (five with pleural effusions, two with pericardial effusions, and one with both) were extremely high, especially in pericardial effusions ([mean +/- SD] pleural effusions, 531.9+/-285.4 pg/mL; pericardial effusion, 3,071.6+/-81.3 pg/mL). CONCLUSION: We predict that in lung cancer, VEGF production and the abnormality of the coagulation-fibrinolysis system differ depending on the stage of progression of disease. Serum VEGF levels would be affected by PaO(2) levels in lung cancer.     

Serum leptin,prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer

Angiogenesis plays an important role in tumor growth and metastasis in solid tumors. VEGF is an important regulator of tumor angiogenesis. Both leptin and prolactin have also been suggested to have roles in the regulation of angiogenic process. In our study, we measured serum leptin, prolactin and VEGF levels in 30 metastatic, 55 non-metastatic breast cancer patients and 25 control subjects. Serum leptin levels were found to be similar in non-metastatic (38.1+/-19.5 ng/ml), metastatic patients (39.6+/-16.3 ng/ml) and control subjects (35.6+/-13.9 ng/ml) (p>0.05). There was no statistically significant difference between patients with visceral metastasis (44.0+/-16.8 ng/ml) and patients with bone metastasis (35.2+/-15.0 ng/ml) (p>0.05). Serum prolactin levels were found to be similar in non-metastatic (12.2+/-10.7 ng/ml), metastatic patients (11.6+/-8.2 ng/ml) and control subjects (12.3+/-8.1 ng/ml), (p>0.05). Moreover, serum prolactin levels were not different in patients with visceral (11.4+/-8.8 ng/ml) and bone metastasis (11.8+/-8.0 ng/ml), (p>0.05). Metastatic patients had higher serum VEGF levels (249.8+/-154.9 pg/ml), when compared to the non-metastatic patients (138.7+/-59.3 pg/ml) and control subjects (108.4+/-47.7 pg/ml), (p<0.05). There was no difference in serum VEGF levels in non-metastatic patients and control subjects (p>0.05). Patients with visceral metastasis (337.0+/-168.0 pg/ml) had higher serum VEGF levels, when compared to patients with bone metastasis (162.6+71.8 pg/ml), (p<0.05). Serum VEGF activity may be used to evaluate angiogenic and metastatic activity in breast cancer patients. However, serum leptin and prolactin levels does not seem to be related with angiogenic activity and metastasis in breast cancer patients.     

血清VEGF和p53抗体与非小细胞肺癌的相关性研究

目的分析非小细胞肺癌（NSCLC）患者血清VEGF、p53抗体表达水平及其诊断价值。方法采用酶联免疫吸附法（ELISA）检测69例初诊为NSCLC的患者血清VEGF和p53抗体浓度,另有45例健康志愿者作为对照。结果 NSCLC患者血清VEFG和p53抗体均明显高于对照组健康人群（P〈0.001）,两者在病理分型中腺癌最高（P〈0.001）,临床分期中以Ⅳ期最高（P〈0.001）;VEGF与p53抗体浓度值呈正相关（r=0.762,P〈0.001）;两项联合检测全部NSCLC的敏感性为86.9%,高于单项检测（P〈0.001）。结论 NSCLC患者血清VEFG和p53抗体显著增高,检测患者血清这两项指标对于肺癌的临床辅助诊断有着重要意义。     

Increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing cytokine with overexpression in various pathological disorders, including tumour growth, chronic inflammation and tissue repair. Recent studies have shown significantly increased serum levels of VEGF in patients with inflammatory bowel disease. The origin of the circulating VEGF is still unknown. The present investigation examines the VEGF production by peripheral blood mononuclear cells (PBMCs) in patients with inflammatory bowel disease. METHODS: VEGF levels were measured in culture supernatants of unstimulated PBMCs of 27 patients with inflammatory bowel disease and 10 healthy volunteers using a solid phase ELISA. In addition, VEGF serum levels were determined. RESULTS: PBMCs of both active Crohn's disease patients (1142.6+/-483.9 pg/ml, P < 0.001, n = 12) and active ulcerative colitis patients (748.0+/-637.6 pg/ml, P = 0.006, n = 4) produced significantly higher amounts of VEGF compared with PBMCs of healthy volunteers (113.4+/-101.8 pg/ml, n = 10). In addition, there was a significantly increased VEGF production by PBMCs of patients with active disease compared with PBMCs of patients with quiescent Crohn's disease (261.6+/-254.8 pg/ml, P < 0.001, n = 7) and inactive ulcerative colitis (147.7+/-100.3 pg/ml, P = 0.02, n = 4). There was no significant difference in VEGF release between patients with inactive inflammatory bowel disease and healthy controls. CONCLUSIONS: Significantly increased VEGF production by PBMCs was found in patients with active Crohn's disease and active ulcerative colitis. The study helps to clarify one of the origins of the significantly enhanced VEGF serum levels in patients with active inflammatory bowel disease observed in recent studies.     

Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer.

Stimulation of growth of endothelial cells from preexisting blood vessels, i.e., angiogenesis, is one of the essential elements necessary to create a permissive environment in which a tumor can grow. During angiogenesis, the matrix metalloproteinase (MMP) family of tissue enzymes contributes to normal (embriogenesis or wound repair) and pathologic tissue remodeling (chronic inflammation and tumor genesis). The proposed pathogenic roles of MMPs in cancer are tissue breakdown and remodeling during invasive tumor growth and tumor angiogenesis. Tissue inhibitors of metalloproteinases (TIMPs) form a complex with MMPs, which in turn inhibits active MMPs. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are unique among mediators of angiogenesis with synergistic effect, and both can also be secreted by thyroid cancer cells. The goal of the study was to evaluate the plasma blood concentration of VEGF, bFGF, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1, and TIMP-2 in patients with cancer and in normal subjects. Twenty-two patients with thyroid cancers (papillary cancer, 11; partly papillary and partly follicular cancer, 3; anaplastic cancer, 5; medullary cancer, 3) and 16 healthy subjects (controls) were included in the study. VEGF, bFGF MMPs, and TIMPs were evaluated by enzyme-linked immunosorbent assay (ELISA). In patients with thyroid cancer, normal VEGF concentrations (74.29 +/- 13.38 vs. 84.85 +/- 21.71 pg/mL; p > 0.05) and increased bFGF (29.52 +/- 4.99 vs. 6.05 +/- 1.43 pg/mL; p < 0.001), MMP-2 (605.95 +/- 81.83 vs. 148.75 +/- 43.53 ng/mL; p < 0.001), TIMP-2 (114.19 +/- 6.62 vs. 60.75 +/- 9.18 ng/mL; p < 0.001), as well as lower MMP-1 (0.70 +/- 0.42 vs. 3.87 +/- 0.53; p < 0.001) levels have been noted. Increased plasma levels of MMP-3 and MMP-9 were also found in patients with medullary carcinoma. In conclusion, predominance of MMP-2 over TIMP-2 and TIMP-1 over MMP-1 as well as increased concentration of bFGF in peripheral blood are common features in patients with thyroid cancer.     

Vascular endothelial growth factor in acute Kawasaki disease

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is an important regulator of angiogenesis and blood vessel permeability. Kawasaki disease (KD) is characterized by systemic vasculitis with increased vascular permeability, implying a possible role of VEGF in KD. To elucidate the involvement of VEGF in the pathogenesis of KD, we investigated 30 patients with acute KD, comparing the time course of plasma VEGF levels (n = 123) with clinical symptoms and laboratory findings. Compared with control values, the peak levels of plasma VEGF were significantly elevated (38+/-26 vs 244+/-248 pg/ml, p <0.001). The VEGF levels at the appearance of skin rash and/or edema of hands and feet were also elevated to 176+/-163 pg/ml (p <0.001). In 7 patients (23%), the plasma VEGF levels remained increased after the resolution of the skin rash and peripheral edema. The VEGF levels were independent of gamma globulin therapy and levels of serum albumin and C-reactive protein. We also measured the plasma levels of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor alpha, both of which can upregulate VEGF in vitro. The plasma levels of VEGF were highly correlated with those of TGF-beta1 (n = 63, r = 0.73, p <0.001) but not with those of tumor necrosis factor alpha. These findings suggest that the production of VEGF is increased and may be upregulated by TGF-beta1 in acute KD. VEGF may be involved in the hyperpermeability of local blood vessels in acute KD.     

Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients.

OBJECTIVES: Our objectives were to compare angiogenesis soluble factor (ASF) levels in chronic hepatitis C (CHC) patients and healthy individuals, and to investigate potential associations between ASF levels and both histological and biochemical markers of disease progression. METHOD: Thirty-six patients (69% males) positive for HCV-RNA by PCR analysis were included in the study. All patients underwent liver biopsy before treatment. Serum levels of vascular endothelial growth factor (VEGF), soluble Flt-1 and Flk-1 receptors, placental growth factor (PlGF), angiopoietin-2 (Ang-2) and soluble Tie-2 receptor were determined by ELISA. Fifteen healthy subjects were used as controls. RESULTS: In comparison to healthy individuals, CHC patients showed significantly increased serum levels of proangiogenic factors PlGF (22 +/- 5 vs. 18 +/- 8 pg/ml; p < 0.05), Ang-2 (1265 +/- 385 vs. 833 +/- 346 pg/ml; p < 0.005) and sFlt-1 (95 +/- 22 vs. 72 +/- 14 pg/ml; p < 0.0001). Interestingly, in CHC patients serum levels of VEGF and Tie-2 correlated with grade of inflammation, PlGF correlated with stage of fibrosis, and Flt-1 and Flk-1 correlated with serum transaminase levels (p < 0.05 in all cases). CONCLUSIONS: CHC patients showed increased serum levels of ASF, and a significant correlation was shown between serum levels of selected ASFs and grade of inflammation, stage of fibrosis, and transaminase levels.     

Serum levels of vascular endothelial growth factor,basic fibroblast growth factor and endostatin in human metastatic liver tumors

BACKGROUND/AIMS: Angiogenic factors are related to the malignant potential of tumors. This study aimed to investigate the relationship of serum angiogenic factors to liver metastasis. METHODOLOGY: The serum levels of vascular endothelial growth factor, basic fibroblast growth factor and endostatin were measured using EIA in 25 patients with metastatic liver tumors and were compared with those of 12 cancer patients without metastasis and 15 controls. RESULTS: The serum vascular endothelial growth factor concentration was significantly higher in the liver metastasis group (503 +/- 84 pg/mL) than in the no metastasis group (205 +/- 38 pg/mL) and the control group (201 +/- 26 pg/mL). The three groups had similar serum basic fibroblast growth factor concentrations. There was no significant difference in serum levels of endostatin among the liver metastasis group (18.8 +/- 1.5 ng/mL), the no metastasis group (23.9 +/- 4.9 ng/mL), and the control group (17.1 +/- 1.5 ng/mL). CONCLUSIONS: Angiogenic response is more prominent than anti-angiogenic responses in liver metastasis. These findings support the rationale for anti-angiogenesis therapy such as endostatin therapy in patients with liver metastasis.     

Vascular endothelial growth factor levels in active pulmonary tuberculosis

BACKGROUND: Vascular endothelial growth factor (VEGF) is a mediator with potent angiogenic, mitogenic, and vascular permeability-enhancing activities that are specific for endothelial cells. Intense angiogenesis has been found in active pulmonary tuberculosis lesions. OBJECTIVES: To determine whether active pulmonary tuberculosis is associated with increased serum levels of VEGF compared with inactive tuberculosis and VEGF levels in healthy subjects, and to assess the changes in serum VEGF levels before and after therapy. DESIGN: Prospective clinical study. SETTING: Chest clinic of a university hospital, Eskisehir, Turkey. PATIENTS AND MEASUREMENTS: Serum VEGF levels of 44 patients with active pulmonary tuberculosis, 24 patients with inactive pulmonary tuberculosis, and 20 healthy subjects were determined. RESULTS: VEGF levels were increased in active pulmonary tuberculosis patients (mean [+/- SD] VEGF level, 598.03 +/- 298.25 pg/mL) compared to both inactive pulmonary tuberculosis patients (mean VEGF level, 296.98 +/- 115.31 pg/mL) and control subjects (mean VEGF level, 339.67 +/- 74.65 pg/mL). The increase in VEGF level observed in patients with active tuberculosis was statistically significant when compared with levels in two other groups (p < 0.001 for both). Serum VEGF levels were statistically different before treatment and after treatment in 10 patients who were observed from diagnosis to the end of treatment (p < 0.01). CONCLUSIONS: Increased serum VEGF levels may be an indicator of active pulmonary tuberculosis, since levels were higher in patients with active pulmonary tuberculosis and were lower after successful treatment. The role of VEGF-mediated angiogenesis in the pathogenesis and progression of pulmonary tuberculosis lesions should be further elucidated.     

Vascular endothelial growth factor in pleural fluid.

STUDY OBJECTIVES: The purpose of this study was to analyze the relationship of the pleural fluid vascular endothelial growth factor (VEGF) level with the diagnostic category and with the pleural fluid characteristics in a group of 70 patients. DESIGN: The VEGF levels of consecutive patients undergoing therapeutic thoracentesis were determined with an enzyme-linked immunosorbent assay. SETTING: University-affiliated tertiary care center. RESULTS: The median level of pleural fluid VEGF in the patients with congestive heart failure (150 pg/mL) was significantly (p < 0.05) lower than the median level in the patients with coronary artery bypass grafting (357 pg/mL), which in turn was significantly lower (p < 0.05) than the median levels in the patients with malignancy (1,097 pg/mL). The overlap between groups, however, limits the diagnostic usefulness of pleural fluid VEGF levels. The VEGF level was most closely correlated with the lactate dehydrogenase level (r = 0.42, p < 0.001) and was also significantly correlated with the total pleural fluid protein level. The median VEGF levels in the pleural fluid of patients with breast cancer were significantly lower (p = 0.017) than in those with lung cancer. The VEGF level was very high (3,294 pg/mL) in the one patient with pulmonary embolism. CONCLUSIONS: We conclude that the VEGF levels in pleural fluid differ significantly from one diagnostic category to another with the highest median levels occurring in patients with malignant pleural effusions. We speculate that VEGF may be responsible for the pleural fluid accumulation in at least some situations.     

Serum TNF-related and weak inducer of apoptosis levels in septic shock patients

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds. In sepsis, this feature is fundamentally altered. We have previously reported elevated levels of angiopoietin-2 in patients with septic shock, and have investigated tumor necrosis factor (TNF)-related and weak inducer of apoptosis (TWEAK), which mediates both angiogenesis and inflammation, in those patients. Enzyme-linked immunoassay was used to measure serum TWEAK levels in 20 patients with septic shock, all of whom were treated by direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX), and in 20 non-septic controls. The TWEAK levels were higher in patients with septic shock (192.8 ± 230.5 pg/mL) than in controls (84.1 ± 28.7 pg/mL, P = 0.043). Between 11 survivors and 10 non-survivors, there was no significant difference in the serum TWEAK levels before the DHP-PMX therapy. During DHP-PMX therapy, however, the serum TWEAK levels were significantly increased in non-survivors (142.2 ± 88.1 pg/mL to 399.0 ± 307.1 pg/mL, P = 0.022). There was a significant correlation between the serum TWEAK levels and white blood cell counts (r = 0.393, P < 0.001), platelet counts (r = 0.418, P < 0.001), or serum CRP levels (r = 0.259, P = 0.029), but there was no correlation between the serum TWEAK levels and blood pressure. The serum TWEAK levels were also correlated with the ratio of angiopoietin-2 to -1 (r = 0.464, P < 0.001). TWEAK may be a suitable marker of disease severity and mortality in septic patients, and TWEAK levels may be associated with vascular permeability via angiopoietin balance.