Serum Concentrations Of bFGF Research Articles

Association between clinical features and course of systemic sclerosis and serum interleukin-8, vascular endothelial growth factor, basic fibroblast growth factor, and interferon alpha.

Certain mediators, such as soluble growth factors and cytokines, among others, are implicated in the immunopathogenesis of systemic sclerosis (SSc). This study aimed to examine the association between serum levels of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), interferon alpha (IFN-α), and basic fibroblast growth factor (bFGF) and the clinical presentation and course of SSc. This longitudinal, observational study included 43 patients with SSc and 24 healthy subjects. Serum concentrations of VEGF, IL-8, IFN-α, and bFGF were measured at baseline in patients previously treated for SSc. Medical history of patients was analyzed retrospectively at the time of cytokine measurement to infer clinical correlations, and during follow-up for a median of 5 years, assessing the incidence of death or cancer. The bFGF and IFN-α concentrations differed between SSc patients and controls (p < 0.01). In turn, organ involvement and SSc phenotypes did not impact studied cytokine concentrations, similar to systemic steroid and/or immunosuppressant use at enrollment. However, we have documented a positive correlation between the current oral steroid dose and serum levels of IL-8 and bFGF. Furthermore, patients with a VEGF level ≥95.7 pg/mL and IFN-α level ≥3.6 pg/mL required cyclophosphamide therapy more often, currently or in the past (approx. 3-fold and 4-fold, respectively). Substantially elevated VEGF and IFN-α concentrations at baseline were associated with higher cancer occurrence (n = 4) during follow-up, while elevated circulating IL-8 level was associated with an increased risk of death (n = 9). The SSc group was characterized by higher serum concentrations of bFGF and IFN-α compared to healthy controls. Patients treated with cyclophosphamide or receiving higher systemic steroid doses, thus suffering from a more severe disease type, had increased cytokine levels. Elevated circulating IFN-α and VEGF levels might be correlated with cancer, whereas raised IL-8 levels may be associated with an increased risk of death. However, further research is needed to verify our findings.

Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy.

BackgroundIn this study we sought to determine if application of bone morphogenic protein 7 (BMP-7) promotes physiological bone healing of non-unions and to investigate if serum cytokine analysis may serve as a promising tool in the analysis of adjunct non-union therapy. Therefore we analyzed the influence of BMP-7 application on the serum cytokine expression patterns on patients with impaired bone healing compared to patients that showed proper bone healing.MethodsOur study involved analyzing blood samples from 208 patients with long bone fractures together with patients that subsequently developed non-unions. From this large pool, 15 patients with atrophic non-union were matched to 15 patients with atrophic non-union treated with local application of BMP-7 as well as normal bone healing. Changes in the cytokine expression patterns were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd week. The patients were followed both clinically and radiologically for the entire duration of the study. Serum cytokine expression levels of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were analyzed and compared.ResultsSerum expression of TGF-β were nearly parallel in all three groups, however serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). bFGF serum concentrations increased initially in patients with proper bone healing and in those treated with BMP-7. Afterwards, values decreased; bFGF serum concentrations in the BMP-7 group were significantly higher than in the other groups (p < 0.05). PDGF serum concentration levels were nearly parallel in all groups, serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05).ConclusionTreatment with BMP-7 in patients with former non-unions led to similar cytokine expression patterns after treatment as those found in patients with proper bone healing. Our results suggest that treatment with BMP-7 promote healing of non-unions. Furthermore, quantitative measurement of serum cytokine expression is a promising tool for evaluating the effectiveness of additional non-union therapies such as adjunct application of growth factors.

Effects of acid–base balance and high or low intensity exercise on VEGF and bFGF

The purpose of the present study was to compare the acute hormonal response to a short-term high-intensity training (HIT) versus a high-volume endurance training (HVT) and to investigate the effects of acid-base status on cytokines involved in angiogenesis (VEGF and bFGF). Eleven subjects participated in three experimental trials. Two times subjects performed four 30-s "all-out" exercise bouts on a cycle ergometer separated by 5-min rest each, at which subjects either received bicarbonate (HIT (B)) or a placebo (HIT (P)) before the exercise. The third exercise trail consisted of a constant load exercise for 1 h at 50% peak power output (PPO). Venous blood samples were taken under resting conditions, 10, 60, and 240 min after each exercise condition to determine VEGF and bFGF serum concentrations. Capillary blood samples were taken to determine lactate concentrations and blood gas parameters. Mean pH values were significantly higher during HIT (B) compared to HIT (P). Serum VEGF concentration was significantly increased 10-min post-exercise in both HIT interventions. HVT showed no significant effects on VEGF levels. The diminished acidosis during HIT (B) had no effects on the VEGF response. There were no significant changes in bFGF in response to HIT or HVT. The present study suggests that HIT is a stimulus for exercise-induced VEGF secretion. These findings might be relevant for the arrangement of training, due to the fact that most of the training is often performed at low intensities possibly leading to an insufficient stimulus for VEGF secretion and angiogenesis.

The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)

BackgroundHyperbaric oxygen (HBO) therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); their in-vivo function is still not fully understood.MethodsForty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO.ResultsThere was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature.ConclusionsA significant effect of HBO on serum concentrations of bFGF and VEGF was not verified in the present study. Additional application of exogenous growth factors in conjunction with HBO was not obviously linked by a coherent cause-and-effect chain as far as wound healing is concerned.

The systemic angiogenic response during bone healing

Angiogenesis is known to be a critical and closely regulated step during bone formation and fracture healing driven by a complex interaction of various cytokines. Delays in bone healing or even nonunion might therefore be associated with altered concentrations of specific angiogenic factors. These alterations might in turn be reflected by changes in serum concentrations. To determine physiological time courses of angiogenic cytokines during fracture healing as well as possible changes associated with failed consolidation, we prospectively collected serum samples from patients who had sustained surgical treatment for a long bone fracture. Fifteen patients without fracture healing 4 months after surgery (nonunion group) were matched to a collective of 15 patients with successful healing (union group). Serum concentrations of angiogenin (ANG), angiopoietin 2 (Ang-2), basic fibroblast growth factor (bFGF), platelet derived growth factor AB (PDGF-AB), pleiotrophin (PTN) and vascular endothelial growth factor (VEGF) were measured using enzyme linked immunosorbent assays over a period of 24 weeks. Compared to reference values of healthy uninjured controls serum concentrations of VEGF, bFGF and PDGF were increased in both groups. Peak concentrations of these cytokines were reached during early fracture healing. Serum concentrations of bFGF and PDGF-AB were significantly higher in the union group at 2 and 4 weeks after the injury when compared to the nonunion group. Serum concentrations of ANG and Ang-2 declined steadily from the first measurement in normal healing fractures, while no significant changes over time could be detected for serum concentrations of these factures in nonunion patients. PTN serum levels increased asymptotically over the entire investigation in timely fracture healing while no such increase could be detected during delayed healing. We conclude that fracture healing in human subjects is accompanied by distinct changes in systemic levels of specific angiogenic factors. Significant alterations of these physiologic changes in patients developing a fracture nonunion over time could be detected as early as 2 (bFGF) and 4 weeks (PDGF-AB) after initial trauma surgery.

Enhanced angiogenesis by gelatin hydrogels incorporating basic fibroblast growth factor in rabbit model of hind limb ischemia

Recently we have developed new sustained release system of basic fibroblast growth factor (bFGF) using gelatin hydrogel as a carrier. Using this system, we examined the effect of topical sustained release of bFGF on angiogenesis and tissue blood perfusion in a rabbit model of hind limb ischemia. Thirty-two rabbits underwent excision of right femoral artery under general anesthesia. Two weeks later the rabbits were randomized into four groups (n = 8 each): no treatment, intramuscular injection of gelatin hydrogel alone, and intramuscular injection of gelatin hydrogel incorporating 30 microg and 100 microg of bFGF. Four weeks after each treatment, selective angiography, tissue blood flowmetry using laser Doppler perfusion imaging, and histological examination of thigh muscle were performed. In groups treated with bFGF incorporating gelatin hydrogel, tissue blood flow, number of arterioles, and vascular density were significantly increased in a dose-dependent manner 4 weeks after the treatment. Serum concentrations of bFGF and vascular endothelial growth factor were not elevated 4 weeks after the treatment. In conclusion, sustained release of bFGF using gelatin hydrogel augmented angiogenesis and improved tissue blood flow after excision of the femoral artery.

Evaluation of the levels of bFGF, VEGF, sICAM-1, and sVCAM-1 in serum of patients with thyroid cancer.

Tumour growth and development depend on a complex cascade of angiogenic factors. The aim of the study is evaluation of the level of growth factors VEGF and bFGF, and adhesion molecules sICAM-1, sVCAM-1 in the serum of patients with papillary thyroid cancer. The study comprised 35 patients aged 21-68 years (mean age 46+/-14) who had papillary thyroid cancer diagnosed on the basis of thin needle aspiration biopsy, and were qualified for operative treatment. This group comprised 28 women and seven men. The control group was 26 healthy individuals. Serum concentrations of bFGF, VEGF, sICAM-1, and sVCAM-1 were evaluated by the enzyme-linked immunosorbent assay (ELISA) method. We have observed significantly higher mean concentrations of bFGF, VEGF, and sICAM-1 in the serum of patients with thyroid cancer compared with the control group. There was no significant difference between the sVCAM-1 concentrations of the thyroid cancer group and the control group.

Serum levels of basic fibroblast growth factor reflect disseminated disease in patients with testicular germ cell tumors.

The potential role of angiogenesis stimulators in the pathogenesis of different tumor entities has been confirmed in several studies. We measured the serum levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in 51 patients with testicular germ cell tumors and in 39 healthy volunteers. Serum concentrations of bFGF, VEGF and PDGF-AB were determined by enzyme-linked immunosorbent assay. The median serum bFGF level for tumor patients was 3.46 pg/ml (range 0-61.6) compared to 0.7 pg/ml (0-11) in the control group (P<0.01). In patients with metastatic disease, the median serum bFGF level was 10.3 pg/ml (0-61.6) in contrast to 2.8 pg/ml (0-50) in patients with localized disease (P<0.01). The median serum VEGF and PDGF levels were 270 pg/ml (0-1,903) and 37,837 pg/ml (9,075-108,800), respectively, for tumor patients and 200 pg/ml (44-585) and 23,000 pg/ml (4,250-70,650) in the control group ( P<0.05). Our data suggest that angiogenesis, as reflected by serum concentrations of bFGF, VEGF and PDGF, plays a functional role in the growth and progression of testicular germ cell tumors.

BASIC FIBROBLAST GROWTH FACTOR AND HYPERTENSIVE DISORDERS IN PREGNANCY

Objective: We examined serum concentrations of basic fibroblast growth factor (bFGF) in women with hypertensive disorders in pregnancy and analyzed whether serum concentrations of bFGF can be used as a discriminator between mild and severe preeclampsia. Methods: One hundred and twenty pregnant women were included in this prospective cohort study. We evaluated serum concentrations of bFGF in pregnant women with chronic hypertension (n=22), mild preeclampsia (n=40), severe preeclampsia (n=31), and healthy pregnant women (n=27). Results: Median serum concentrations of bFGF in healthy pregnant women, women with chronic hypertension, and women with mild or severe preeclampsia were 0.0 (0–37.2), 0.0 (0–3.0), 1.7 (0–97.2), and 0.0 (0–52.0), respectively. Comparison of the median values of serum bFGF concentrations showed a significant difference between healthy pregnant women and women with mild preeclampsia (P=0.02). In a logistic regression model, we found a significant influence of bFGF serum concentrations on the diagnosis of mild preeclampsia (P=0.01), but not on the diagnosis of chronic hypertension (P=0.19) or severe preeclampsia (P=0.41). Conclusions: Elevated serum concentrations of bFGF are associated with mild preeclampsia, but are not discriminatory for the distinction between mild and severe preeclampsia.

Angiogenic peptides in prostatic disease.

To determine the value of measuring serum concentrations of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with benign prostatic hyperplasia (BPH), advanced and localized prostate cancer, and thus assess the role of angiogenesis factors as markers of malignancy and the formation of metastasis. Serum was obtained from 106 suitable patients who attended a routine clinic during the study period. A histological diagnosis was confirmed for each patient and a bone scan was positive in those with metastatic disease. The level of serum prostate specific antigen (PSA) was measured and the serum concentrations of VEGF and bFGF measured using a quantitative sandwich immunoassay technique. There was a significant difference (1.6-fold) in the serum concentration of bFGF between patients with local and advanced prostate cancer (P=0.006), but there was no significant difference for either of the growth factors between patients with BPH and metastatic prostate cancer (Mann-Whitney test). The serum levels of VEGF and bFGF could not be used to distinguish benign from malignant prostatic disease; the serum PSA level is of more value than either, but the serum concentration of bFGF may be of some value in differentiating patients with local and advanced malignancy.

Physiologically assessed coronary collateral flow and intracoronary growth factor concentrations in patients with 1- to 3-vessel coronary artery disease.

The purpose of this study was to test the hypothesis that there is a relation between collateral flow and intracoronary concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and that the combined concentrations of both growth factors and the extent of coronary artery disease (CAD) play a role as covariables in such an association. In 76 patients undergoing balloon angioplasty, a collateral flow index (CFI, no units) was determined with sensor-tipped guidewires. Simultaneously, serum concentrations of bFGF and VEGF, obtained at the aortic root from the ostium of the collateralized coronary artery (n = 76) and from the distal position of the occluded coronary artery (n = 34), were determined. There was a direct correlation between CFI and distal VEGF (r = 0.33, P = 0.05) but not bFGF concentrations. Focusing on the proximal sampling site, there was a direct correlation between CFI and both bFGF (r = 0.29, P = 0.01) and VEGF concentrations (r = 0.44, P < 0.0001). The sum of the concentrations of both growth factors was directly associated with CFI irrespective of the proximal (r = 0.51, P < 0.0001) or distal sampling site (r = 0.34, P = 0.048). There was a trend toward higher proximal VEGF concentrations in patients with higher numbers of coronary stenotic lesions (r = 0.25, P = 0.03). In patients with CAD, there is an association between a directly measured index of collateral flow and intracoronary concentrations of bFGF and VEGF. This direct relation is dependent on the site of blood sampling within the coronary artery tree. The association is closest when the combined bFGF and VEGF concentrations are taken into account. In the case of VEGF, it is influenced by the degree of coronary atherosclerosis.

Enhancement of bFGF export associated with malignant progression of human salivary gland cell clones.

Using 2 in vitro systems in which normal human salivary gland cells can be immortalized by transfection with SV40 DNA (NS-SV-DC), and in which a non-metastasizing human salivary gland adenocarcinoma cell clone (HSGc) can be converted to biologically aggressive and metastasizing cancer cells, we analyzed the relationship between the expression of basic fibroblast growth factor (bFGF) and malignant phenotype in human salivary gland cell clones. By enzyme immunoassay, intracellular contents of bFGF were equally detected in all the cell clones, while bFGF contained in serum-free conditioned medium of each cell clone was different: HSGc and metastasizing cell clones, respectively, released 2- and 10-fold more bFGF into media than did NS-SV-DC. Immunoblot analysis also revealed a similar result as that detected by enzyme immunoassay. By Northern blot analysis, bFGF mRNA expression was consistently detected in all the cell clones examined. We then quantitated bFGF contents in sera of tumor-bearing mice by enzyme immunoassay. Although sera from nude mice bearing an HSGc tumor showed significantly higher amounts of bFGF than those of control mice, bFGF concentrations in sera gradually decreased after removal of the tumor. For metastasizing cell clones, serum concentrations of bFGF were 2.2- to 2.6-fold higher than those of HSGc. In addition, bFGF amounts in sera after removal of the tumors were significantly higher in mice bearing metastasizing cell clone tumors compared with those of HSGc tumor-bearing mice. Our results, therefore, indicate that increase in bFGF release occurs along with the progression of human salivary gland cancer cells and that serum bFGF may be useful for evaluation of tumor presence.

Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas.

Basic fibroblast growth factor (bFGF) is a potent mitogenic and angiogenic factor that is known to regulate GH, PRL, and TSH secretion. Sequences within a bFGF gene family member have been detected in transforming DNA samples derived from human PRL-secreting tumors. Furthermore, elevated serum concentrations of bFGF have been noted in patients with multiple endocrine neoplasia-1. To further examine the significance of bFGF in sporadic human pituitary adenomas, we investigated the expression of bFGF by these tumors. Using an enzyme-linked immunoassay that recognizes all 16-24 kilodalton molecular mass forms of bFGF, we measured circulating serum concentrations in 21 patients with sporadic pituitary adenomas; they ranged from less than 0.5-84 pg/mL and declined following surgical adenomectomy. To confirm the pituitary source of this growth factor, we determined in vitro bFGF release from 43 adenomas (10 GH, 7 PRL, 10 ACTH, 14 gonadotrope adenomas/oncocytomas, and 2 silent subtype 3 adenomas). bFGF was present with wide variability (0.75-2100 pg/24 h.10(5) cells) in conditioned culture media of all adenomas examined. The adenohypophysial source of this growth factor was further demonstrated by the reverse hemolytic plaque assay. Variable bFGF messenger RNA expression was identified by the reverse-transcription polymerase chain reaction technique in 9 functional (2 PRL, 5 GH, 2 ACTH) and 7 nonfunctional (1 oncocytoma, 2 null cell, 2 gonadotrope, 2 Silent Subtype 3) adenomas examined. bFGF levels were unaltered in vitro following hypothalamic hormone stimulation/inhibition. The lack of a bFGF signal peptide sequence and hypothalamic hormone-independence suggest that secretion of this factor may be independent of pituitary hormone regulation. Immunocytochemistry failed to localize bFGF in tumors that released this factor in vitro, suggesting that storage of this peptide does not correlate with its synthesis and release. In conclusion, the heterogenous expression of bFGF suggests that it may play a specific and selective role in the tumorigenic process of some pituitary adenomas.