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.     

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.     

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.     

Serum Levels of IL-10 and IL-22 Cytokines in Patients with Psoriasis

Background: As a chronic inflammatory condition, psoriasis results from an interaction between genetic and immunologic factors in a predisposing environment. In spite of compelling evidence for the role of T cells and cytokines in psoriasis, interleukin (IL)- 10 and IL-22 have not been sufficiently investigated. Objective: To assess the serum levels of IL-10 and IL-22 in patients with psoriasis compared to healthy controls. Methods: A total of 28 patients with psoriasis were compared with 28 age and sexmatched healthy subjects. Psoriasis Area and Severity Index (PASI) criteria were used to measure the severity of the disease. Serum levels of IL-10 and IL-22 were measured in both groups and compared. Results: The mean serum level of IL-10 was 89.5±18.7 in patients compared to 117.2±23.4 pg/ml in the controls (p=0.36). Also, serum level of IL-22 was 284.1±49.7 in patients versus 425.4±82.8 pg/ml in control group (p=0.17). There was a significant direct correlation between levels of IL-10 and IL-22 in patients group (p=0.0005). The clinical severity of psoriasis was significantly correlated with high levels of IL-22 (p<0.0001).Conclusions: The decreased levels of IL-10 in psoriatic patients and direct correlation between higher levels of IL-22 and disease severity support the clinical implication of both cytokines in psoriasis.     

Reductions of circulating matrix metalloproteinase 2 and vascular endothelial growth factor levels after treatment with pegvisomant in subjects with acromegaly

BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in activation of the matrix metalloproteinase (MMP) system; the latter is implicated in atherosclerosis and cardiovascular disease. Patients with acromegaly have reduced life expectancy primarily due to cardiac disease. AIM: This study assessed plasma MMPs and VEGF levels in patients with active acromegaly (IGF-I > 130% upper limit of normal), and on treatment with pegvisomant. SUBJECTS AND METHODS: Twenty patients [nine female, mean age 56.1 +/- 13.8 yr (mean +/- sd)] were studied at baseline and on pegvisomant therapy and compared with data from 25 healthy volunteers (12 female; 56.6 +/- 14.2 yr). Plasma MMP-2, MMP-9, and VEGF levels were measured. RESULTS: Serum IGF-I fell from a baseline (mean +/- sd) level of 620.1 +/- 209.3 ng/ml to 237.5 +/- 118.5 ng/ml on pegvisomant (doses 10-60 mg; P < 0.001). MMP-2 levels at baseline were significantly higher in patients compared with healthy controls (380.7 +/- 204.8 vs. 207.4 +/- 62.6 ng/ml; P < 0.001), but with treatment a significant reduction in MMP-2 [380.7 +/- 204.8 vs. 203.0 +/- 77.4 ng/ml; P < 0.001] and VEGF (283.4 +/- 233.6 vs. 229.1 +/- 157.4 pg/ml; P = 0.008) was noted. There was no significant difference in MMP-9 levels between patients and controls at baseline (797.5 +/- 142.1 vs. 788.3 +/- 218.0 ng/ml; P = 0.87) or between baseline and posttreatment levels (797.5 +/- 142.1 vs. 780.0 +/- 214 ng/ml; P = 0.76). CONCLUSIONS: Our novel data demonstrate that treatment of acromegaly with pegvisomant leads to reductions in MMP-2 and VEGF concentrations. Further studies are required to determine the significance of these findings with relation to cardiac disease.     

Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis

Vascular endothelial growth factor (VEGF) is a potent angiogenesis mediator. Scant reports are available defining the role of VEGF in active and inactive tubercular meningitis (TBM) with no studies on brain tuberculoma. We quantified VEGF levels by enzyme linked immunoassay (ELISA) in cerebrospinal fluid (CSF) and serum in 20 cases each with active and inactive TBM as well as 22 cases of intraparenchymal tuberculoma. VEGF expression and microvessel angiogenesis quantification was done in 7 cases where tuberculomas were excised. Significantly increased VEGF levels in CSF were found in active TBM cases (106.0+/-50.0 pg/ml) compared to inactive TBM cases (14.7+/-10.0 pg/ml) (p<0.001). Mean serum VEGF levels in active TBM, inactive TBM and tuberculoma were 694.93+/-820.66 pg/ml, 499.61+/-238.33 pg/ml and 541.0+/-389.0 pg/ml, respectively. Immunohistochemical staining of excised tuberculoma demonstrated high expression of VEGF in granulomatous areas with intense positivity in inflammatory mononuclear cells, Langhan's giant cells as well as reactive astrocytes and fibrocytes. A strong positive correlation was observed between microvessel density and VEGF expression. Serial decrease in serum VEGF levels was observed with increasing duration of therapy in tuberculoma. We conclude that increased CSF and serum VEGF levels are a measure of activity of the disease in neurotuberculosis and its gradual decrease over a period of time is probably an indicator of therapeutic response.     

Soluble TRAIL concentrations are raised in patients with systemic lupus erythematosus

BACKGROUND: Increased apoptosis may induce autoimmune conditions. Apoptosis is induced by binding of death receptor ligands, members of the tumour necrosis factor (TNF) superfamily, to their cognate receptors. The Fas-Fas ligand pathway has been studied extensively in relation to systemic lupus erythematosus (SLE). However, other death pathways are also considered important. TNF related apoptosis inducing ligand (TRAIL), another ligand of the TNF superfamily, induces apoptosis in sensitive cells. OBJECTIVE: To assess soluble (s) TRAIL concentrations in sera of SLE patients. METHODS: 40 SLE patients were studied (20 with active and 20 with inactive disease). Serum sTRAIL concentrations were measured by a solid phase sandwich enzyme linked immunosorbent assay. Levels in SLE patients were compared with those in patients with rheumatoid arthritis (n = 20), Wegener's granulomatosis (n = 20), and healthy controls (n = 20). RESULTS: Mean (SEM) serum sTRAIL concentration in SLE patients (936.0 (108.2) pg/ml) was higher than in healthy controls (509.4 (33.8) pg/ml; p<0.01) or in disease control patients with rheumatoid arthritis (443.8 (36.1) pg/ml, p<0.001) or Wegener's granulomatosis (357.1 (32.2) pg/ml; p<0.001). The mean serum sTRAIL concentration was 1010.2 (168.0) pg/ml for patients with inactive disease and 861.8 (138.7) pg/ml for those with active disease. sTRAIL values were not correlated with specific manifestations of the disease, such as leucopenia or lymphopenia, or with SLE disease activity index. CONCLUSIONS: Serum sTRAIL concentrations are increased SLE patients. This seems to be disease specific and could indicate a role for TRAIL in SLE pathophysiology.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

 Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20 pg/ml versus 61 ± 8 pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36 pg/ml versus 413 ± 49 pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258 pg/ml; HGF, 1500 ± 295 pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94 pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43 pg/ml; HGF, 1294 ± 224 pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients. Received: February 19, 2002 / Accepted: August 13, 2002 Acknowledgment We are grateful to Ms. Aki Nomura for assistance with the ELISA of VEGF and HGF.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

Abstract

Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20?pg/ml versus 61 ± 8?pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36?pg/ml versus 413 ± 49?pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258?pg/ml; HGF, 1500 ± 295?pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94?pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43?pg/ml; HGF, 1294 ± 224?pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients.     

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.     

Interleukin 12 in Takayasu's arteritis: plasma concentrations and relationship with disease activity

OBJECTIVE: To investigate plasma concentrations of interleukin 12 (IL-12) and their relationship with disease activity in patients with Takayasu's arteritis (TA). METHODS: IL-12 levels were determined by quantitative enzyme immunoassay in the plasma of 80 patients with TA, 25 age/sex matched healthy controls, and 15 followup patients with active TA on immunosuppressive therapy. RESULTS: Significantly increased levels of IL-12 were observed in patients with TA versus controls (90.6 +/- 365.3 vs 6.9 +/- 11.3 pg/ml; p < 0.05) and in patients with active versus inactive TA (168.7 +/- 507.0 vs 12.6 +/- 26.9 pg/ml; p = 0.005). The prevalence of IL-12 (the cytokine levels above cutoff value) was higher in patients than in controls [44% (35/80) vs 12% (3/25); p < 0.01] and in patients with active versus inactive TA [57% (23/40) vs 30% (40); p < 0.05]. Six of the 9 patients who became inactive on followup also had normalized levels of IL-12. CONCLUSION: The data indicate that IL-12 might be an important mediator of inflammation in TA.     

Normal levels and function of endothelial progenitor cells in patients with psoriatic arthritis

Endothelial progenitor cells (EPCs) are a population of bone marrow derived cells which have been attributed with the ability to migrate into areas of tissue ischemia and to posses reparative qualities. EPCs have been shown to be decreased in level and function in various inflammatory disorders. Psoriasis and psoriatic arthritis are associated with an increase in cardiovascular morbidity. The aim of the study was to investigate the number of EPCs among patients suffering from psoriasis and psoriatic arthritis. Patients suffering from active psoriasis and psoriatic arthritis were recruited as well as healthy controls. Disease activity was assessed with the DAS-28, BASDAI and PASI scores. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using the CD34/133 and CD34/KDR. No significant difference was found between numbers of EPCs between healthy controls, patients with psoriasis and psoriatic arthritis. A significant correlation was found between levels of VGEF and the BASDAI score. The results of the current study do not support a significant role for EPCs in the pathogenesis of psoriasis and psoriatic arthritis.     

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 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.     

Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality; however, some patients with OSA do not develop cardiovascular disease even in the presence of severe nocturnal oxygen desaturations. Vascular endothelial growth factor (VEGF) is a hypoxia-sensitive glycoprotein stimulating neoangiogenesis. We hypothesized that VEGF production is increased in OSA because of repetitive nocturnal hypoxia. Three different groups were investigated: 10 OSA patients with severe nighttime hypoxia (Group A), 10 OSA patients with moderate hypoxia (Group B), and 10 healthy volunteers (Group C). Serum levels of VEGF were measured by ELISA from peripheral venous blood samples obtained at 7 AM. Group A had significantly (p < 0.01) increased VEGF serum levels when compared with Group B and Group C (mean +/- SEM: 410 +/- 77 pg/ml versus 224 +/- 38 pg/ml and 245 +/- 61 pg/ml). The degree of nocturnal oxygen desaturation in OSA significantly correlated with the VEGF concentrations (r = 0.67, p < 0.01). In conclusion, serum levels of VEGF are elevated in severely hypoxic patients with OSA and are related to the degree of nocturnal oxygen desaturation. This might constitute an adaptive mechanism to counterbalance the emergence of OSA-related cardiovascular disease.     

Urine leukotriene E4 levels are elevated in patients with active systemic lupus erythematosus.

The peptidoleukotrienes, leukotriene (LT) C4 and its metabolites LTD4 and LTE4, cause diverse physiologic effects and have been implicated in several disease processes. A potential role for enhanced peptidoleukotriene synthesis in the pathogenesis of autoimmune disease in general and systemic lupus erythematosus (SLE) in particular has been suggested by animal studies. Therefore, we measured the urinary levels of LTE4 in patients with active and inactive SLE as well as in patients with rheumatoid arthritis (RA), scleroderma (Scl), and in healthy controls. Comparisons were made to other standard clinical tests in assessing individual patient disease activity. A marked increase in urinary LTE4 levels in patients with active SLE was noted (319 +/- 49 pg/mg creatinine, n = 20) relative to patients with inactive SLE (80 +/- 8 pg/mg creatinine, n = 7 [p less than 0.02]), patients with RA (86 +/- 8 pg/mg creatinine [p less than 0.01]), and healthy controls (68 +/- 4.3 pg/mg creatinine, n = 6 [p less than 0.01]). Patients with Scl also had elevated urinary LTE4 levels (188 +/- 33 pg/mg creatinine, n = 7) relative to controls (p less than 0.02), while values from patients with RA were not significantly different from controls. Using the Systemic Lupus Activity Measurement as a gauge of clinical activity, a rise in urinary LTE4 levels was noted during stages of active disease with a subsequent decline following the resolution of these symptoms. Our data indicate that increased synthesis of leukotrienes is associated with active SLE and Scl and suggest that these leukotrienes may mediate certain symptoms associated with these diseases.     

The value of serum interferon-gamma level in the differential diagnosis of active and inactive pulmonary tuberculosis

Interferon (IFN)-gamma plays a pivotal role in protective immunity against Mycobacterium tuberculosis. Elevations of IFN-gamma have been found in the affected lung and bloodstream of patients with pulmonary tuberculosis. In the present study, we aimed to investigate the role of serum IFN-gamma level in the differential diagnosis of active and inactive pulmonary tuberculosis. Fourty seven patients with newly diagnosed active pulmonary tuberculosis, 21 patients with inactive pulmonary tuberculosis, and 20 healthy volunteers were enrolled in the study. Serum samples were collected from each subject and stored at - 70 degrees C until the analysis of IFN-gamma. The mean value of IFN-gamma levels were 9.3 +/- 4.6 pg/mL in patients with newly diagnosed pulmonary tuberculosis, 9.8 +/- 3.8 pg/mL in patients with inactive tuberculosis, and 10.2 +/- 3.4 pg/mL in healthy controls. The comparison of IFN-gamma levels of the three groups was not found statistically significant (p= 0.4). Serum IFN-gamma level was not found to be valuable in the differential diagnosis of active and inactive pulmonary tuberculosis.     

Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis

OBJECTIVE: To determine whether elevated levels of the angiogenic cytokine vascular endothelial growth factor (VEGF), detected on presentation to an early arthritis clinic, are associated with the development of chronic and erosive arthritis. METHODS: Concentrations of VEGF and its soluble receptor, soluble fms-like tyrosine kinase 1 (sFlt-1), were measured by enzyme-linked immunosorbent assay in serum samples from patients with early (<2 years from onset) arthritic symptoms in the peripheral joints, namely early rheumatoid arthritis (RA), self-limiting arthritis (viral, reactive, and idiopathic inflammatory arthritis), or psoriatic arthritis. In addition, measurements were made in random samples from patients with longstanding (>3 years from symptom onset) RA treated with disease-modifying antirheumatic drugs, from patients with osteoarthritis (OA), and from patients with polyarthralgia without arthritis, as well as from nonarthritic controls. RESULTS: Serum VEGF levels at presentation were elevated in patients with inflammatory arthritis (RA, psoriatic, and self-limiting arthritis) as well as in patients with OA, in comparison with nonarthritic controls. Moreover, serum VEGF concentrations were significantly higher in patients with early RA than in patients with self-limiting arthritis. Serum VEGF levels at presentation in patients with early RA correlated significantly with the development of radiographic damage after 1 year. Improvement in the clinical symptoms of RA was associated with a reduction in serum VEGF levels. Serum sFlt-1 levels were raised in patients with early and longstanding RA and in those with self-limiting arthritis, and correlated positively with the serum VEGF concentrations in patients with inflammatory arthritis. CONCLUSION: These findings implicate the proangiogenic cytokine VEGF in the persistence of inflammatory arthritis, and support the hypothesis that expansion of the synovial vasculature is important for the development of joint destruction in RA.     

Increased circulating vascular endothelial growth factor is correlated with disease activity in polyarticular juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the relevance of vascular endothelial growth factor (VEGF) in the pathogenesis of juvenile rheumatoid arthritis (JRA). METHODS: Serum VEGF levels in 58 patients with JRA (systemic in 17, polyarticular in 29, pauciarticular in 12) were measured by ELISA and compared with those of 21 patients with infectious diseases and 50 healthy children. Correlations of VEGF levels with number of joints with active arthritis, erythrocyte sedimentation rate (ESR), and hyaluronic acid (HA) were examined. RESULTS: Serum levels of VEGF in patients with JRA were significantly higher than in healthy controls. Patients with systemic and polyarticular JRA showed statistically higher levels of VEGF than those with infectious diseases. VEGF levels correlated statistically with C-reactive protein (CRP) in patients with both infectious diseases and polyarticular JRA, but the regression slope (VEGF/CRP) was much steeper in polyarticular JRA than in infectious diseases. Serum VEGF levels correlated with disease activity variables such as the number of joints with active arthritis, ESR, and serum HA levels in polyarticular JRA. CONCLUSION: The correlation of serum VEGF levels and disease activity in polyarticular JRA suggests that VEGF may take an active part in joint inflammation.     

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.