Serum TGF-beta1 Levels Research Articles

Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice

The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine's effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy. Four groups of C57/Bl6 mice received 14 Gy thoracic radiation. Mice were treated with taurine or saline supplementation by gavage. After 10 days and 14 weeks of treatment, TGF-beta1 levels were measured in serum and bronchoalveolar lavage fluid (BALF). Lung collagen content was determined using hydroxyproline analysis. Ten days post radiotherapy, serum TGF-beta1 levels were significantly lower after gavage with taurine rather than saline (P = 0.033). BALF TGF-beta1 at 10 days was also significantly lower in mice treated with taurine (P = 0.031). Hydroxyproline content was also significantly lower at 14 weeks in mice treated with taurine (P = 0.020). This study presents novel findings of taurine's role in protecting from TGF-beta1-associated development of lung fibrosis after thoracic radiation.

Primary aldosteronism can alter peripheral levels of transforming growth factor β and tumor necrosis factor α

Primary aldosteronism (PA) is the most common secondary cause of hypertension that has recently been implicated in alterations of the immune system and progression of cardiovascular disease. To study the cytokines transforming growth factor beta1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10) in patients with PA and essential hypertensives (EH) and evaluate its association with the renin-angiotensin-aldosterone system. We studied 26 PA and 52 EH patients as controls, adjusted by their blood pressure, body mass index, age, and gender. In both groups, PA and EH, we measured serum aldosterone (SA), plasma renin activity (PRA), and cytokines TGF- beta1, TNF-alpha, and IL-10. In addition, 17 PA patients were treated for 6 months with spironolactone, a mineralocorticoid receptor (MR) antagonist. PA patients had lower levels of TGF-beta1 (17.6+/-4.1 vs 34.5+/-20.5 pg/ml, p<0.001) and TNF-alpha (17.0+/-4.4 vs 35.6+/-21.7 pg/ml, p<0.001) and similar IL-10 levels (99.7+/-18.7 vs 89.4+/-49.5 pg/ml, p: ns), as compared with EH controls. TGF-beta1 and TNF-alpha levels showed a remarkable correlation with SA/PRA ratio in the total group (PA+EH). The treatment of PA patients with spironolactone increased the TGF-beta1 levels (18.3+/-5.9 to 28.4+/-6.3 pg/ml, p<0.001), while TNF-alpha, and IL-10 remained unchanged. Our results showed that PA patients have lower TGF-beta1 and TNF-alpha cytokine serum levels than EH. TGF-beta1 levels were restored with spironolactone, showing a MR-dependent regulation. In this way, the chronic aldosterone excess modifies the TGF-beta1 levels, which could produce an imbalance in the immune system homeostasis that may promote an early proinflammatory cardiovascular phenotype.

Circulating transforming growth factor-β1 levels and the risk for kidney disease in African Americans

Transforming growth factor-β1 (TGF-β1) is well known to induce progression of experimental renal disease. Here we determined whether there is an association between serum levels of TGF-β1 and the risk factors for progression of clinically relevant renal disorders in 186 black and 147 white adults none of whom had kidney disease or diabetes. Serum TGF-β1 protein levels were positively and significantly associated with plasma renin activity along with the systolic and diastolic blood pressure in blacks but not whites after controlling for age, gender and body mass index. These TGF-β1 protein levels were also significantly associated with body mass index and metabolic syndrome and more predictive of microalbuminuria in blacks than in whites. The differential association between TGF-β1 and renal disease risk factors in blacks and whites suggests an explanation for the excess burden of end-stage renal disease in the black population but this requires validation in an independent cohort. Whether these findings show that it is the circulating levels of TGF-β1 that contributes to renal disease progression or reflects other unmeasured factors will need to be tested in longitudinal studies.

Serum and tissue expression of transforming growth factor beta 1 in psoriasis

In psoriasis, keratinocyte hyperplasia may be explained by imbalance of growth factors responsible for epidermal proliferation and altered metabolism of their receptors. Transforming growth factor-beta 1 (TGF-beta1) implications in the pathogenesis of psoriasis can be attributed to several mechanisms besides keratinocyte cell cycle inhibition. To evaluate the relation between serum and tissue levels of TGF-beta1 in psoriasis and their correlation with disease parameters. Serum and punch biopsy of involved and non-involved skin of 22 patients with psoriasis vulgaris and 10 controls were collected for quantification of TGF-beta1 by enzyme-linked immunosorbent assay kit. Serum level of TGF-beta1 in psoriatic patients was higher than controls in a statistically non-significant manner. Correlations between serum level of TGF-beta1 and extent of the disease (P = 0.007) and Psoriasis Area and Severity Index (PASI) score (P = 0.005) were observed. Mean tissue levels of TGF-beta1 were highest in psoriatic lesions in contrast to normal skin of psoriatic patients and healthy controls, but not statistically significant. Correlation between tissue levels of TGF-beta1 in non-involved skin and extent of the disease (P = 0.007) and PASI score (P = 0.013) was detected. Correlation was detected between levels of TGF-beta1 in psoriatic plaques and serum of patients (P = 0.035), but not between levels of TGF-beta1 in non-involved skin and serum. Tissue expression of TGF-beta1 in psoriasis may be affected by the stage of development of the lesion. The direct relation between TGF-beta1 in psoriatic plaques and serum imply that the mechanisms for TGF-beta1 production and release in both these compartments may be related.

Variations in serum transforming growth factor-beta1 levels with gender, age and lifestyle factors of healthy Japanese adults.

Elevated serum or plasma Transforming Growth Factor-β1 (TGF-β1) levels have been linked to cancer and other diseases in numerous studies; however, very few studies have reported an association between circulating TGF-β1 and lifestyle factors in healthy people. We examined the association between serum TGF-β1 levels and gender, age, body mass index (BMI), smoking, and drinking in a large population-based cohort study (N = 9,142). Serum TGF-β1 levels were detected by the Quantikine enzyme-linked immunoassay kit (R&D Systems). The data indicated highly significant (p<0.0001) difference in serum TGF-β1 levels between men (mean value: 37.6 ± 0.12 ng/mL, N = 4888) and women (mean value: 35.1 ± 0.12 ng/ml, N = 4254). Serum TGF-β1 levels decreased with age (trend p < 0.0001) and were positively associated with obesity (trend p < 0.0001) in both men and women. We observed a significant trend with increased serum TGF-β1 levels corresponding to increased amount of tobacco and alcohol consumption in men (trend p < 0.0001). These findings suggest that serum TGF-β1 levels appear to be modulated by gender, age and lifestyle factors such as obesity, cigarette smoking, and alcohol drinking in healthy Japanese adults.

Correlation between anti-fibrotic effect of baicalin and serum cytokines in rat hepatic fibrosis

To investigate the correlation between the antifibrotic effect of baicalin and serum cytokine production in rat hepatic fibrosis. Forty male Sprague-Dawley rats were divided randomly into four groups: normal control group, model group, baicalin-treated group, and colchicine-treated group. Except for the normal control group, all rats in the other groups were administered with carbon tetrachloride to induce hepatic fibrosis. At the same time, the last two groups were also treated with baicalin or colchicine. At the end of the 8 wk, all animals were sacrificed. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10 were measured. Liver index, hepatic hydroxyproline content and the degree of liver fibrosis were also evaluated. The levels of ALT, AST and liver index in the baicalin-treated group were markedly lower than those in the model group (ALT: 143.88 +/- 14.55 U/L vs 193.58 +/- 24.35 U/L; AST: 263.66 +/- 44.23 U/L vs 404.37 +/- 68.29 U/L; liver index: 0.033 +/- 0.005 vs 0.049 +/- 0.009, P < 0.01). Baicalin therapy also significantly attenuated the degree of hepatic fibrosis, collagen area and collagen area percentage in liver tissue (P < 0.01). Furthermore, the levels of serum TGFbeta1, TNF-alpha and IL-6 were strikingly reduced in the baicalin-treated group compared with the model group, while the production of IL-10 was up-regulated: (TGF-beta1: 260.21 +/- 31.01 pg/mL vs 375.49 +/- 57.47 pg/mL; TNF-alpha: 193.40 +/- 15.18 pg/mL vs 260.04 +/- 37.70 pg/mL; IL-6: 339.87 +/- 72.95 pg/mL vs 606.47 +/- 130.73 pg/mL; IL-10: 506.22 +/- 112.07 pg/mL vs 316.95 +/- 62.74 pg/mL, P < 0.01). Baicalin shows certain therapeutic effects on hepatic fibrosis, probably by immunoregulating the imbalance between profibrotic and antifibrotic cytokines.

Serum levels of transforming growth factor-β1 in patients with mild psoriasis vulgaris and effect of treatment with biological drugs

Psoriasis is an immune cell-mediated disease in which cytokines play an important role. Studies have been performed to explore the relationship between the disease and cytokine blood levels with a view to finding a biomarker for monitoring disease severity/activity and treatment efficacy. To investigate the levels of transforming growth factor-beta1 (TGF-beta1) in patients with mild psoriasis vulgaris (PV) and the possible use of this cytokine in monitoring treatment with biological drugs. Serum levels of TGF-beta1 were estimated in 33 untreated patients (PI group), in 7 of these patients (PII group) before and after 3 months of treatment with one of two biological drugs (etanercept and efalizumab) and in 19 healthy volunteers (control group). Significantly (P < 0.0001) higher serum levels of TGF-beta1 were found in the PI group [Psoriasis Area and Severity Index (PASI) 9-10] compared with the 19 healthy volunteers. In the PII group, after the administration of one of the biological drugs, a 50% reduction in PASI and a significant (P = 0.032) decrease in TGF-beta1 was noted. Raised TGF-beta1 levels in patients with mild PV decreased in tandem with a decrease in PASI after biological drug treatment. Hence, TGF-beta1 levels seem to be sensitive to changes in disease severity.

Serum Transforming Growth Factor-β1 and Epidermal Growth Factor in Biliary Atresia

Biliary atresia (BA) is a serious liver disease in children. Since transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) are involved in the hepatic reparative process, our objective was to investigate whether serum TGF-beta1 and serum EGF levels were associated with therapeutic outcomes in BA. Serum levels of TGF-beta1 and EGF were determined with the ELISA method in 67 postoperative BA patients with a median age of 7 years and in 10 age-comparable healthy children. The BA patients were then divided into two groups depending on their therapeutic outcome: good outcome (jaundice-free) and poor outcome (persistent jaundice). Clinical data, serum TGF-beta1 and serum EGF levels were compared between the two groups of BA patients. Correlation analysis of serum TGF-beta1 with serum EGF was carried out. Data are expressed as mean +/- SD. Serum TGF-beta1 levels of BA patients were higher than those of controls (86.6 +/- 15.7 vs. 75.7 +/- 8.8 ng/ml, p = 0.0362). However, there was no difference in serum EGF between BA patients and controls (133.1 +/- 66.6 vs. 125.4 +/- 88.9 pg/ml, p = 0.744). Further subgroup analysis showed that patients with good outcomes (n = 40) had higher serum TGF-beta1 and serum EGF levels than patients with poor outcomes (TGF-beta1: 91.2 +/- 16.5 vs. 79.6 +/- 11.7 ng/ml, p = 0.002; EGF: 148.5 +/- 65.0 vs. 110.3 +/- 63.4 pg/ml, p = 0.02). In addition, serum TGF-beta1 was positively correlated with serum EGF (Pearson's r = 0.3418, p = 0.0046). Elevated serum TGF-beta1 and serum EGF levels were associated with a good outcome in BA patients. There was a positive correlation between serum TGF-beta1 and serum EGF. This suggests that the resultant TGF-beta1 and EGF pathways may be involved in the pathophysiological process in postoperative BA.

Association between a TGFβ1 promoter polymorphism and the phenotype of aspirin-intolerant chronic urticaria in a Korean population

Chronic urticaria/angioedema is a common phenotype in patients with aspirin sensitivity; however, its genetic mechanism is not understood. Transforming growth factor (TGF)beta1 is a key regulatory cytokine involved in allergic inflammation. We examined the association of a TGFbeta1 genetic polymorphism with aspirin-intolerant chronic urticaria (AICU) and aspirin-tolerant chronic urticaria (ATCU) in a Korean population. A promoter polymorphism in the TGFbeta1 gene, TGFbeta1 -509C>T, was analysed in 112 AICU patients, 153 ATCU patients and 457 normal controls (NC), and the frequency was compared among the groups. Serum TGFbeta1 levels were measured by ELISA. The minor allele frequency of the -509C>T polymorphism was significantly higher in patients with AICU compared with the other two groups (P < 0.02 for AICU vs. NC; P < 0.05 for AICU vs. ATCU). Among the AICU patients, those with the T allele tended to have lower serum TGFbeta1 levels. These findings suggest that the -509C>T polymorphism in the TGFbeta1 promoter may contribute to the development of the AICU phenotype.

Local Inflammation Exacerbates Cyclosporine A-Induced Gingival Overgrowth in Rats

Gingival overgrowth (GO) is a common side effect of long-term cyclosporine A (CsA) treatment. The risk factors appraised include drug interactions with calcium channel blockers, age, cyclosporine dose, dental bacterial plaque, duration of treatment, and genetic predisposition. The relationship and mechanism between GO and local inflammation caused by dental bacterial plaque have not been clearly defined. This research was carried out to investigate the histomorphometrical alterations and serum levels of transforming growth factor beta1 (TGF-beta1) in CsA-induced GO with or without local inflammation. Thirty-four male Sprague-Dawley rats were divided into 4 groups: Group I (control); Group II (ligation); Group III (CsA); Group IV (ligation and CsA). After 9 weeks the rats were sacrificed. The morphological examination was made and the histological changes with hematoxylin and eosin (HE) staining were observed. TGF-beta1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). We report here that obvious GO are found in Group III and Group IV after CsA treatment, especially those rats with existed gingivitis presented an aggravation of GO. TGF-beta1 levels in CsA-exposed groups were significantly higher than untreated groups, but ligation did not affect TGF-beta1 level. These findings suggest that CsA-induced GO can be exacerbated by local inflammation. TGF-beta1 may be a key factor for the development of GO.

The role of CD4+CD25+ regulatory T cells in the pathogenesis of chronic abacterial prostatitis/chronic pelvic pain syndrome

To explore the role of CD4+CD25+ regulatory T cells in the pathogenesis of chronic abacterial prostatitis/chronic pelvic pain syndrome (CAP/CPPS). Peripheral blood samples were collected from 45 CAP/CPPS patients and 18 healthy age-matched male persons. Peripheral blood mononuclear cells (PBMCs) were isolated. The percentages of CD4+CD25+ and CD4+CD25high regulatory T cells were detected by flow cytometry. PCR was used to examine the mRNA expression of Foxp3, a transcription factor expressed in the CD4+CD25+ cells. ELISA was used to examine the plasma level of tumor growth factor (TGF)-beta1. There were no significant differences in the percentages of peripheral blood CD4+CD25+ and CD4+CD25highT cells between the CAP/CPPS patients and normal control group (both P>0.05). The Foxp3 mRNA in the PBMCs of the CAP/CPPS IIIA and CAP/CPPS IIIB patients were (0.69+/-0.23) and (0.44+/-0.18) respectively, both significantly lower than that of the control group [(1.37+/-0.19), P<0.05]. The serum TGF-beta1 levels of the CAP/CPPS IIIA and CAP/CPPS IIIB patients were (18.09+/-10.45) pg/ml and (14.06+/-6.22) pg/ml respectively, both significantly lower than that of the control group [(27.01+/-13.29) pg/ml, both P<0.05]. Not the number of peripheral blood CD4+CD25+ regulatory T cells, but its defective function participates in the pathogenesis of CAP/CPPS. The Foxp3 gene and TGF-beta1 play important roles in the process of pathogenesis of CAP/CPPS too.

Investigation of Soluble HER2 and Transforming Growth Factor Beta-1 Serum Levels in Gestational Trophoblastic Disease

HER2/neu and TGF-beta1 are over-expressed in various types of malignancies. It appears that they play an important role in the biologic behavior of tumors and have prognostic value. Gestational tropoblastic diseases (GTDs) comprise of a heterogeneous group characterized by abnormally proliferating trophoblastic tissues, ranging from benign to malignant. The objective of this study was to measure and compare the serum levels of s-HER2 and TGF-beta between patients with GTDs and pregnant and non-pregnant controls. Serum levels of s-HER2 and TGF-beta1 were determined by ELISA method in 95 GTD patients (55 complete moles, 32 persistent moles, and 8 choriocarcinoma), 30 normal pregnant controls, and 22 normal non-pregnant controls. Mean serum level of s-HER2 did not differ significantly between patients and controls. TGF-beta1 serum level was significantly higher in GTD patients (20.29 +/- 10.68 pg/ml with 95% confidence interval (CI) of 18.10-22.48 pg/ml) compared with pregnant controls (10.26 +/- 11.84 pg/ml with 95% CI of 5.75-14.76 pg/ml) and non-pregnant controls (7.27 +/- 9.61 pg/ml with 95% CI of 3.01-11.53 pg/ml) (P < 0.001). Our findings suggest that TGF-beta1 serum levels in GTD patients may represent a potential prognostic marker. Further investigations with larger sample size and more frequent sampling are required to elucidate this issue.

Increased Circulating Fibrocytes in Asthma with Chronic Airflow Obstruction

A proportion of patients with asthma present with chronic airflow obstruction (CAO). We hypothesized that this effect may result from increased activity of circulating fibroblast-like progenitor cells (fibrocytes) that could home to the airway mucosal wall. To compare the proportion, proliferation, and differentiation of circulating fibrocytes from patients with asthma with CAO or no airflow obstruction (NOA) and control subjects. We investigated circulating fibrocytes in 11 patients with asthma with CAO and a rapid decline in FEV(1), 9 patients with asthma with NOA, and 10 nonasthmatic control subjects. Blood nonadherent non-T (NANT) cells were incubated with fetal calf serum or each patient's own serum and fibrocytes expressing CD34, CD45, and collagen I with alpha-smooth muscle actin were identified by flow cytometry. A higher percentage of circulating fibrocytes in NANT cells was found in patients with CAO when compared with patients with NOA and control subjects. In CAO, the slope of the yearly decline in FEV(1) correlated with circulating fibrocytes (r = -0.756, n = 11, P < 0.01). When NANT cells from patients with CAO were cultured in the patients' own sera, more fibrocytes were detected than when cultured in sera from patients with NOA or from normal subjects. An anti-transforming growth factor (TGF)-beta(1)-neutralizing antibody inhibited alpha-smooth muscle actin-positive fibrocyte transformation from NANT cells of patients with CAO. Serum TGF-beta(1) levels were higher in patients with CAO than in patients with NOA or in normal subjects. Circulating fibrocytes are increased in patients with asthma with CAO and can be transformed by TGF-beta(1) to myofibroblasts. Fibrocytes may contribute to airway obstruction in asthma.

Boosting BCG vaccination with MVA85A down-regulates the immunoregulatory cytokine TGF-β1

In clinical trials recombinant-modified vaccinia virus Ankara expressing the Mycobacterium tuberculosis antigen 85A (MVA85A) induces approximately 10 times more effector T cells than any other recombinant MVA vaccine. We have found that in BCG primed subjects MVA85A vaccination reduces transforming growth factor beta 1 (TGF-β1) mRNA in peripheral blood lymphocytes and reduces TGF-β1 protein in the serum, but increases IFN-γ ELISPOT responses to the recall antigen SK/SD. TGF-β1 is essential for the generation of regulatory T cells and we see a correlation across vaccinees between CD4+CD25hiFoxP3+ cells and TGF-β1 serum levels. This apparent ability to counteract regulatory T cell effects suggests a potential use of MVA85A as an adjuvant for less immunogenic vaccines.

Polymorphisms of the IL12B and IL23R Genes Are Associated with Psoriasis

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.

Influence of Feixian Formula on serum transforming growth factor-β1 and platelet-derived growth factor in rats with bleomycin-induced pulmonary fibrosis

To observe the effects of Feixian Formula, a compound traditional Chinese herbal medicine for treating pulmonary fibrosis, on bleomycin-induced pulmonary fibrosis in rats, and its influence on serum transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor (PDGF). Seventy-two male Wistar rats were infused with bleomycin (1 mg/kg) through tracheal intubation to induce pulmonary fibrosis, and they were randomly divided into untreated group (n=24), prednisone-treated group (n=24) and Feixian Formula-treated group (n=24). Fifteen male Wistar rats of the sham-operated group were infused with equivalent normal saline. Twenty-four hours after operation, prednisone (5 mg/kg) and Feixian Formula (1.25 g/kg) were given to the prednisone-treated group and Feixian Formula-treated group respectively by intragastric administration once a day. Equivalent saline was administered to rats of the untreated group and sham-operated group. On the 14th, 28th and 45th day, 5 rats in the sham-operated group and 8 rats in each of the other three groups were dissected to observe pathologic changes of the lung tissues, and the levels of serum TGF-beta1 and PDGF were determined by enzyme-linked immunosorbent assay. At the 45th day, the degree of pulmonary interstitial fibrosis was lesser in rats of the Feixian Formula-treated group as compared with those of the untreated group and prednisone-treated group. The levels of serum TGF-beta1 and PDGF were increased, and were significantly higher than those of the sham-operated group, especially on the 45th day (P<0.05). Changes of TGF-beta1 level in the prednisone-treated group and the Feixian Formula-treated group were similar to untreated group (P>0.05), and there was no significant difference between the prednisone-treated group and the Feixian Formula-treated group (P>0.05). PDGF in the Feixian Formula-treated group reached the highest level on the 14th day, significantly higher than those of the other three groups (P<0.01). Then it decreased, and was close to that of the sham-operated group on the 45th day (P=0.792). The levels of PDGF in untreated group and prednisone-treated group were increased depending on time, and were obviously higher than that of the sham-operated group on the 45th day (P<0.01). Feixian Formula can relieve bleomycin-induced pulmonary fibrosis in rats, and the mechanism of its action may be related to down-regulating serum PDGF.

A Systemic Combination Therapy with Granulocyte-Colony Stimulating Factor Plus Erythropoietin Aggravates the Healing Process of Balloon-Injured Rat Carotid Arteries

Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Aim of our study was to evaluate the impact of a maximised 7 day-combination therapy with G-CSF plus EPO on the healing process following balloon injury of the rat carotid artery. Osmotic pumps to systemically deliver G-CSF and EPO at saturating doses during the first seven days post injury were implanted into the peritoneal cavity of splenectomised male Sprague-Dawley rats. Cytokine treatment resulted in significantly elevated numbers of white blood cells, hematocrit levels, circulating hematopoietic stem cells, and-temporarily-circulating endothelial precursors. Functional reendothelialisation as assessed by Evan's blue staining on day 14 post injury was not affected by the cytokine treatment. The neointimal response was analysed on day 7 and 28 post injury, and was significantly higher at the day 7 timepoint (Cytokines: I/M-ratio 1.10+/-0.09 vs. Saline: 0.36+/-0.06). Cytokine treated rats also displayed higher rates of thrombotic occlusion (Cytokines: 25-33% vs. Saline: 0%). Serum levels of PAI-1, TGFbeta1, and PDGF-BB were not elevated in the cytokine treated rats. The proliferative rates both in the injured vessel wall and the surrounding adventitia as assessed by BrdU incorporation were significantly higher in the cytokine treated animals. The number of CD45(pos) hematopoietic cells was significantly higher in the adventitia of the cytokine treated rats. Vasa vasorum were not found to be significantly different. The increased neointimal response was not due to expression of G-CSF- or EPO-receptors on VSMCs within the vessel wall or myofibroblasts in the adventitia. The systemic administration of G-CSF plus EPO during the first week after balloon-injury impairs the vascular healing process by increasing the neointimal response and the risk for thrombotic occlusion.

Increased Survival From Stage IV Melanoma Associated With Fewer Regulatory T Cells

Melanoma often elicits a profound immune response, and this response has been exploited by various immune therapies. These immunotherapies ultimately fail, however, and advanced melanoma is uniformly fatal, suggesting the development of an immune escape mechanism. In this study, markers of immune escape including regulatory T cells (T(regs)), dendritic cells (DCs), and TGF-beta were evaluated in 14 Stage IV melanoma patients and correlated with survival. Peripheral blood mononuclear cells were isolated from Stage IV melanoma patients and analyzed for T(regs) and DCs by flow cytometry using fluorescent CD3, CD4, CD25, Lin, HLA-DR, CD11c, and CD123 antibodies. Serum TGF-beta levels were evaluated by ELISA from these patients. Clinical data were extracted from the patients' medical records. Stage IV melanoma patients with shorter survival (less than 24 mo) had a significantly higher proportion of T(regs) than those with longer survival (15% versus 8%, respectively, P = 0.004). The numbers of DCs and the serum TGF-beta levels were not significantly different in these two groups. There was an inverse relationship between the percentage of T(regs) and survival, although this did not reach statistical significance (r = -0.35, P = 0.22). There was also an inverse relationship between peripheral T(regs) and DCs. When patients were divided into groups of greater than or less than 7% T(regs), the number of total DCs was higher in the patients with fewer T(regs) than in those with more T(regs), but this did not reach statistical significance (16,535 versus 12,126 total DCs/mL, P = 0.52). In Stage IV melanoma patients, a high percentage of T(regs) appears to be associated with shorter survival. The inverse relationship of the number of DCs and T(regs) in these patients may provide an insight to the origin of this observation.

Laminin and transforming growth factor beta-1 in children with vesicoureteric reflux

High-grade vesicoureteric reflux (VUR) promotes the development of renal nephropathy (RN) due to scar formation. This process involves transforming growth factor beta-1 (TGF beta(1)), which stimulates production of the extracellular matrix proteins, including laminin (LN). The aim of the study was to assess LN and TGF beta(1) concentration according to VUR grade. The study group (1) consisted of 54 patients aged 6.23 +/- 4.15 years with VUR, including: A, 19 with grade II; B, 19 with grade III; and C, 16 with grades IV or V reflux. The control group (2) contained 27 healthy patients aged 6.76 +/- 4.02 years. LN and total TGF beta(1) concentrations in serum and urine were determined by the immunoenzymatic (EIA) method. To assess total serum TGF beta(1) levels, we used a solid-phase enzyme-linked immunosorbent assay (ELISA). Both serum and urinary levels of LN and TGF beta(1) in VUR patients were higher compared with controls (p < 0.05). The highest urinary concentration of LN and TGF beta(1) was found in subgroup C. A positive correlation was noted between urinary TGF beta(1) and LN. Increased TGF-beta(1) and LN levels in urine of high-grade VUR children suggests a potential role in fibrogenesis. Further trials are needed to investigate the role of serum and urinary LN level in VUR children.

Serum transforming growth factor-ß1 as a risk stratifier of sudden cardiac death

Sudden cardiac death prematurely claims the lives of some 7 million each year worldwide. It occurs primarily in patients with an underlying structural cardiac abnormality, and regardless of the type of the underlying pathology (heart failure, dilated and hypertrophic cardiomyopathies, myocardial infarction and aging), death is almost always caused by ventricular tachycardia (VT) which rapidly degenerates to ventricular fibrillation (VF). Implantable cardioverter defibrillator is an effective but expensive therapy for preventing SCD, and finding a reasonably specific, sensitive and cost-effective risk stratification tool for patients at high risk of sudden cardiac death will have great clinical utility in preventing premature sudden cardiac death. Increased myocardial fibrosis has been shown to develop in a wide range of cardiac diseases all manifesting increased risk of VT and VF. Clinical and experimental studies attribute a major role for fibrosis in the initiation of VT, VF and sudden cardiac death. Transforming growth factor-beta1 (TGF-beta1) has been shown to promote myocardial tissue fibrosis and perhaps more importantly in cardiac conditions associated with increased myocardial fibrosis are shown to be positively correlated with increased serum levels of TGF-beta1. In the present hypothesis we suggest that monitoring the serum levels of TGF-beta1 may be a cost-effective risk stratifier to identify patients at high risk of sudden cardiac death caused by VT and VF.