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.     

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.     

Spider angiomas in Patients with liver Cirrhosis:Role of vascular endothelial growth factor and basic fibrobalast 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 (L22±13 vs. 71±11 pg/mL, P=0.003for 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.     

High levels of serum basic fibroblast growth factor in children with biliary atresia

BACKGROUND/AIMS: The purpose of this study was to investigate the relationship between basic fibroblast growth factor (bFGF) and clinical outcome in biliary atresia (BA) patients after surgical treatment. METHODOLOGY: Sixty-five pediatric patients with BA post Kasai operation and 12 healthy children were recruited. The patients were categorized into 2 groups according to their serum levels of total bilirubin (TB < 2, no jaundice vs. TB > or = 2mg/dL, persistent jaundice) and alanine aminotransferase (ALT < 100 vs. ALT > or = 100 U/L). The serum bFGF levels were determined by enzyme-linked immunosorbent assay. RESULTS: The mean serum bFGF level of the BA patients was higher than that of normal controls (14.2 +/- 1.6 vs. 9.0 +/- 2.2 pg/mL, p < 0.03). Serum bFGF levels in the persistent jaundice group were significantly higher than those without jaundice (17.6 +/- 3.1 vs. 11.9 +/- 1.5 pg/mL, p < 0.04). Additionally, patients with serum ALT > or = 100 U/L had higher serum levels of bFGF than those with serum ALT < 100 U/L (19.0 +/- 2.4 vs. 8.9 +/- 1.6 pg/mL, p < 0.0005). In the no jaundice group, serum bFGF levels were significantly elevated in the patients with portal hypertension (PH) compared with those without PH (15.8 +/- 2.2 vs. 8.6 +/- 1.9 pg/mL, p < 0.02). CONCLUSIONS: The significant elevation in bFGF levels is associated with the presence of PH and the severity of hepatic damage. bFGF may play a role in the pathogenesis of progressive inflammation and the perpetuation of PH in BA patients after Kasai procedure.     

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 hepatocyte growth factor in patients with peripheral arterial occlusive disease.

Hepatocyte growth factor (HGF) is a multifunctional protein implicated in tissue regeneration, wound healing, and angiogenesis. We measured serum HGF concentrations in 37 patients with peripheral arterial occlusive disease (PAOD). Among them, 36 patients underwent arteriography. Serum HGF concentrations were also measured in 40 control subjects who remained free of vascular, liver, kidney, or lung disease. Patients with PAOD showed elevated serum HGF concentrations compared with control subjects (0.40+/-0.02 vs. 0.19+/-0.01 ng/mL; P<0.001). Serum HGF concentrations were significantly higher in smokers compared with nonsmokers (0.45+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.003). The serum HGF concentrations in patients with collaterals tended to be higher than those in patients without collaterals (0.43+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.06). Moreover, in patients who underwent bypass surgery or angioplasty, serum HGF concentrations decreased from 0.41+/-0.03 to 0.21+/-0.04 ng/mL after treatment (P<0.001). Serum HGF may be an useful marker for the diagnosis of PAOD. HGF may play an important role in angiogenesis and collateral vessel growth in PAOD.     

Obesity is associated with increased levels of circulating hepatocyte growth factor

OBJECTIVES: This study evaluated whether obesity in humans was associated with an increase in circulating hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels. BACKGROUND: Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Adipose tissue is able to secrete multiple cytokines and growth factors ex vivo. We hypothesized that the increased presence of adipose tissue in obese subjects results in systemic elevations of the mitogenic factors HGF and VEGF. METHODS: Blood samples were obtained from lean (n = 21) and obese (n = 44) volunteers. Serum HGF and VEGF levels were assessed by enzyme-linked immunoadsorbent assay. Insulin and fasting glucose levels were measured to evaluate insulin sensitivity. Conditioned medium of adipose cells was assayed for HGF secretion. RESULTS: Serum HGF levels in obese subjects were more than three-fold higher than those of lean subjects (2,462 +/- 184 pg/ml vs. 765 +/- 48 pg/ml, p < 0.0001). The VEGF levels were not significantly elevated in obese subjects (135 +/- 31 pg/ml vs. 128 +/- 37 pg/ml). The HGF concentrations, but not VEGF concentrations, were significantly correlated with body mass index (BMI) (p < 0.0001, r = 0.74). The observed increases in HGF concentrations of obese subjects were not secondary to insulin resistance or hypertension. Freshly isolated human adipose cells secreted HGF. CONCLUSIONS: Our results indicate that obesity is associated with a marked increase in circulating HGF levels, which correlate linearly with BMI. Because vascular growth factors have been associated with the pathogenesis of atherosclerosis, the possible role of such humoral factors as a link between obesity and cardiovascular disease is very intriguing.     

High serum hepatocyte growth factor level in patients with non-Hodgkin's lymphoma

Higher pretreatment serum hepatocyte growth factor (HGF) levels were observed in patients with multiple myeloma and Hodgkin's disease, but not in those with non-Hodgkin's lymphoma (NHL). We examined patients' serum levels at diagnosis using enzyme-linked immunosorbent assay and histological expression of HGF in pathological specimens of lymphoma, in relation to clinical features. The subjects were 77 NHL patients and 40 healthy controls. The serum levels of HGF in NHL patients at diagnosis were significantly higher than those in healthy controls (median 1019 vs. 689 pg/mL, P < 0.001). At diagnosis, patients with more than two sites of extranodal involvement (P = 0.001), higher scores of international prognostic index (P = 0.015), and advanced Ann Arbor stage (P = 0.023) had a higher level of serum HGF. Although the association of pretreatment serum HGF level and survival was not significant, a correlation of serial change of serum HGF levels with treatment response was found in limited cases. Furthermore, HGF expression of lymphoma tissues was shown in 18 of 24 (75%) different NHL subtypes, including most of the diffuse large B cell lymphoma (12 of 15, 80%). In conclusion, our study showed higher pretreatment serum HGF levels in NHL patients, which was related to clinical features; and the serial change of HGF seemed to parallel the treatment response. The pathogenic role of HGF in NHL patients was further highlighted by a modest expression of HGF in most of the diffuse large B cell lymphoma.     

Basic fibroblast growth factor changes in response to coronary angioplasty in patients with stable angina

Basic fibroblast growth factor (bFGF) has been implicated in the pathogenesis of coronary atherosclerosis and in angiogenesis. We assessed the changes in serum bFGF before, immediately after, and 6 months after coronary angioplasty (PTCA). Using the ELISA methods we measured plasma bFGF in 28 patients who underwent PTCA, in 20 patients with coronary artery disease who underwent elective coronary angiography and in 28 healthy subjects. Before PTCA and coronary angiography, bFGF plasma levels were similar in both patient groups (4.4+/-1.0 vs. 3.3+/-0.5 pg/ml), but were significantly higher compared with those of the control group (0.8+/-0.1 pg/ml, P<0.05). By 24 h, 3 months and 6 months after PTCA, bFGF levels had decreased significantly in the PTCA group (3.2+/-0.6, 1.7+/-0.3 and 2.7+/-0.6 pg/ml, respectively, P<0.05). In conclusion, these findings show that bFGF levels are elevated in patients with coronary artery disease. Following PTCA, bFGF levels decreased significantly and remained stable for 6 months after the procedure. Thus, bFGF level may change in response to PTCA in patients with coronary artery disease and stable angina.     

Circulating hepatocyte growth factor as a marker of thrombus formation in unstable angina pectoris

A new enzyme-linked immunosorbent assay can detect 10 pg/ml of human hepatocyte growth factor (HGF). Circulating HGF was significantly higher in patients with unstable angina (296+/-184 pg/ml, mean+/-SD, n=36) than in healthy volunteers (201+/-64 pg/ml, n=250, p<0.0001). Individual concentrations exceeded the mean control value +2 SD (329 pg/ml) in 12 of the 36 (33%) patients with unstable angina. The present study indicates that this new, sensitive HGF assay can successfully detect thrombosis in patients with unstable angina.     

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection

OBJECTIVE: Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection. METHODOLOGY: The serum VEGF levels in 46 patients with pulmonary MAC infection were compared with those in 16 normal control subjects. Pulmonary lesions were evaluated using chest CT. In 20 patients, after treatment, serum VEGF levels were measured and chest CT performed again to evaluate pulmonary response to treatment. RESULTS: Infected patients had higher serum VEGF levels than controls (435.2 +/- 29.1 vs. 167.0 +/- 10.6 pg/mL, P < 0.0001), and serum VEGF level correlated with the extent of disease. The serum VEGF levels in 14 patients who underwent treatment and exhibited an improvement in their pulmonary lesions decreased significantly compared with the results pretreatment (509.0 +/- 60.7 vs. 303.6 +/- 65.3 pg/mL, P = 0.0092). In infected patients, alveolar macrophages, epithelioid cells and multinucleated giant cells exhibited VEGF overexpression on immunohistochemical staining. CONCLUSIONS: This study suggests that VEGF may be associated with the pathogenesis of pulmonary MAC infection. Additionally, serum VEGF levels may be a useful surrogate marker for evaluating the extent of disease and of the response to treatment.     

Circulating DNA level is negatively associated with the long-term survival of hepatocellular carcinoma patients

AIM: To quantify the circulating DNA in plasma from patients with hepatocellular carcinoma (HCC) and to evaluate its prognostic value. METHODS: Blood samples were collected from 79 patients with HCC before operation, 20 patients with liver cirrhosis, and 20 healthy volunteers. Circulating DNA was extracted from plasma and quantified. The association between circulating DNA level and prognosis of HCC patients was evaluated. RESULTS: Compared with the healthy volunteers (17.6±9.5 ng/mL), a significant higher circulating DNA level was found in the patients with HCC (47.1±43.7 ng/ mL, P = 0.000) or with liver cirrhosis (30.0±13.3 ng/ mL, P - 0.002). The circulating DNA level was closely associated with tumor size (P = 0.008) and TNM stage (P = 0.040), negatively associated with the 3-year disease-free survival (DFS) (P - 0.017) and overall survival (OS) (P = 0.001). CONCLUSION: Large or invasive tumor may release more circulating DNA, and higher level of circulating DNA may be associated with poor prognosis of HCC patients.     

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.     

Plasma basic fibroblast growth factor and bone marrow fibrosis in clonal myeloproliferative disorders

Basic fibroblast growth factor (bFGF) is an important growth factor involved in clonal hematopoietic expansion, neoangiogenesis, and bone marrow fibrosis, all of which are important pathobiologic features of clonal chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS). The aim of this study was to assess circulating bFGF concentrations in patients with CMPD and MDS with respect to the presence of bone marrow fibrosis in histopathologic examination. The study group comprised 18 patients with CMPD (six female, 12 male; median age 50 years), seven patients with MDS (one female, six male; median age 66 years) and 10 healthy adults as controls (four female, six male; median age 29 years). CMPD group included six chronic myelogenous leukemia (CML), seven essential thrombocythemia (ET), three polycythemia vera (PV), two agnogenic myeloid metaplasia (AMM). All seven MDS patients were the FAB subtype of refractory anemia (RA). Bone marrow biopsy sections stained with hematoxylin and eosin (H & E) and for reticulin were examined for the presence of fibrosis. The median plasma bFGF level was 18.2 pg/ml (interquartile range, IQR: 15.2-26.7) in patients with CMPD, 18.0 pg/ml (IQR: 15.8-26.4) in patients with MDS, 13.6 pg/ml (IQR: 9.9-20.0) in the control group. The bFGF levels were significantly higher in patients with CMPD in comparison with the healthy control group (P = 0.031). Circulating bFGF tended to be significantly lower in relation to the development of marrow fibrosis (P = 0.028). The complicated interactions of bFGF and fibrosis in the context of CMPD may be either 'cause' or 'effect'. The bFGF might represent an important link between angiogenesis, fibrosis, and clonal neoplastic hematopoiesis during the development of CMPD.     

Plasma vascular endothelial growth factor in acute mountain sickness

STUDY OBJECTIVES: To investigate the hypothesis that an increase in circulating vascular endothelial growth factor (VEGF) occurs in mountaineers at high altitude, particularly in association with acute mountain sickness (AMS) and/or low hemoglobin oxygen saturation. DESIGN:: Collection of medical histories, AMS scores, plasma samples, and arterial oxygen saturation (SaO(2)) measurements from mountaineers at 1,500 feet (sea level) and at 14,200 feet. SETTING: Mount McKinley ("Denali"), AK. PARTICIPANTS: Sixty-six mountaineers. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Plasma VEGF at 14,200 feet was not increased in any group. In fact, plasma VEGF was significantly lower in subjects who did not develop AMS (53 +/- 7.9 pg/mL; mean +/- SEM; n = 47) compared to control subjects at sea level (98.4 +/- 14.3 pg/mL; n = 7; p = 0.005). Plasma VEGF at 14, 200 feet for subjects with AMS (62 +/- 12 pg/mL; n = 15) did not differ significantly from subjects at 14,200 feet without AMS, or from control subjects at sea level. Of a small number of subjects with paired specimens at sea level and at base camp (n = 5), subjects who exhibited a decrease in plasma VEGF at 14,200 feet were those who did not develop AMS. Neither SaO(2), prior AMS, AMS symptom scores, or acetazolamide use were correlated with plasma VEGF. CONCLUSIONS: Subjects at high altitude who do not develop AMS have lower plasma VEGF levels compared to control subjects at sea level. Plasma VEGF at high altitude is not elevated in association with AMS or hypoxia. Sustained plasma VEGF at altitude may reflect a phenotype more susceptible to AMS.     

Interleukin-4 inhibits the increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF), a potent angiogenic, permeability-enhancing cytokine plays an important role in tissue repair and chronic inflammatory disorders. Peripheral blood mononuclear cells (PBMCs) and the inflamed mucosa have been demonstrated to be main sources of the recently described circulating VEGF in patients with inflammatory bowel disease (IBD). There is no current information about the influence of immunoregulatory cytokines on VEGF in IBD. The present study examines the effect of interleukin-4 on the increased VEGF production of PBMCs in patients with IBD. METHODOLOGY: Unstimulated PBMCs from 17 patients with Crohn's disease, 16 patients with ulcerative colitis and 8 healthy controls were cultured with or without IL-4. VEGF production was measured in the supernatant using an enzyme-linked immunosorbent assay. RESULTS: IL-4 led to a significant reduction of the VEGF production by PBMCs of both active Crohn's disease patients (471.7 +/- 377.5 pg/mL vs. 208.2 +/- 123.2 pg/mL, P = 0.018, n = 7) and active ulcerative colitis patients (177.1 +/- 79.4 pg/mL vs. 87.4 +/- 77.2 pg/mL, P = 0.008, n = 9). IL-4 inhibited significantly the VEGF production by PBMCs of patients with inactive Crohn's disease (179.2 +/- 133.9 pg/mL vs. 87.7 +/- 56.6 pg/mL, P = 0.005, n = 10). There was no significant difference of VEGF release by PBMCs cultured with IL-4 in patients with active Crohn's disease or active ulcerative colitis compared with PBMCs cultured without IL-4 in patients with inactive disease and healthy controls (112.6 +/- 41.9 pg/mL, n = 8). CONCLUSIONS: IL-4 has been shown to reduce the increased VEGF production of PBMCs in patients with IBD to normal levels. The known defective immunosuppressive effect of IL-4 in IBD may contribute to the pathogenic cascade leading to inflammation by VEGF mediated mechanisms.     

Effects of total coronary artery occlusion on vascular endothieial growth factor and transforming growth factor beta

Vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta1) play an important role in angiogenesis. We wanted to determine if concentrations of growth factors in the coronary sinus (CS) and right atrium (RA) are higher in coronary artery disease patients with total occlusions than in those with partial occlusions. Fifty-one patients scheduled for coronary artery angiography were evaluated for possible recruitment. A 6F Goodale-Lubin catheter was used to collect blood from the CS and RA. Data for all but four patients were gathered successfully, leaving 47 study patients. The reviewer was blinded to growth factor data when interpreting coronary angiographic findings. Of the 47 enrolled patients, 32 had at least one diseased vessel, seven of whom had at least one major total epicardial coronary occlusion. In all 32 patients, the concentrations of VEGF in the CS were higher than those in the RA (31.5 +/- 2.7 vs 27.1 +/- 1.8 pg/mL; p = 0.005). Patients with total occlusions had higher VEGF concentrations in the CS than those with non-total occlusions (38.9 +/- 8.0 vs 29.5 +/- 2.6 pg/mL; p = 0.037). The differences in TGF-beta1 in the two groups were not statistically significant. The higher CS VEGF concentrations in patients with total occlusion indicate that VEGF may play a part in the development of angiogenesis.     

Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients

BACKGROUND: The purposes of this study were to determine soluble angiogenic factors in Crohn's disease (CD) patients and to compare these factors according to the pathological behavior of the disease in order to establish a possible relationship with its evolution in patients with CD. METHODS: Blood samples were collected from 70 patients with CD, grouped according to their phenotypic behavior, and from 30 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), and their cognate receptors [VEGFR1, VEGFR2, and angiopoietin receptor tyrosine kinase (Tie2)] were assayed by ELISA. RESULTS: Circulating levels of VEGF, PlGF, VEGFR1, Ang2, and Tie2 were significantly higher in CD patients than in healthy controls (489 +/- 271 versus 335 +/- 118 pg/mL, P < 0.001; 31 +/- 9 versus 23 +/- 9 pg/mL, P < 0.001; 1.7 +/- 0.4 versus 1.0 +/- 0.3 ng/mL, P < 0.001; 4.8 +/- 2.0 versus 3.9 +/- 2.0 ng/mL, P < 0.05; and 36 +/- 5 versus 22 +/- 7 ng/mL, P < 0.001, respectively). Conversely, CD patients showed significantly lower serum levels of Ang1 than healthy controls (40 +/- 12 versus 67 +/- 22 ng/mL; P < 0.001). No differences between the groups were found in VEGFR2 serum level. The circulating levels of the angiogenic factors did not differ significantly when the CD patients were classified according to pathological phenotype. CONCLUSIONS: In comparison with healthy controls, CD patients were found to have an active angiogenic profile, as detected by significant alterations in levels of angiogenesis soluble markers. These patients did not differ in serum levels of angiogenic factors according to phenotypic disease behavior.