Plasma Transforming Growth Factor-β1 Research Articles

Role of Elevated Plasma Transforming Growth Factor-β1 Levels in Wound Healing

Transforming growth factor (TGF)-beta1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-beta1 have a lower inflammatory response, reduced early extracellular matrix deposition, and reduced later cutaneous scarring, indicating the importance of local tissue TGF-beta1. By contrast, increasing the local, tissue levels of TGF-beta1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-beta1 correlate with increased fibrogenesis in the lung, kidneys, and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-beta1 on wound healing. We used transgenic mice that express high levels of active TGF-beta1 and have elevated plasma levels of TGF-beta1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic, TGF-beta1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-beta3 and TGF-beta-receptor RII and a decrease in immunostaining for TGF-beta1 compared with wounds in control mice. By contrast, the PVA sponges showed the opposite response, with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied by an increase in the immunostaining for all three TGF-beta isoforms and their receptors compared with PVA sponges from control mice. Together, the data demonstrate that increased circulating levels of TGF-beta1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models, subcutaneously implanted PVA sponges and cutaneous incisional wounds, differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF-beta isoforms is critical for control of scarring.

Reduced plasma transforming growth factor-β1 levels in patients with chronic hepatitis C after interferon-α therapy: association with regression of hepatic fibrosis

Background/Aim: Transforming growth factor-β1 is involved in liver fibrosis. Our aim was to examine the association of plasma transforming growth factor-β1 levels with the degree of liver fibrosis. Methods: We analyzed plasma transforming growth factor-β1 levels in 43 patients with chronic hepatitis C treated with interferon-α using a transforming growth factor-β1 ELISA. The content of transforming growth factor-β1 in liver tissue obtained by needle biopsy ( n=13) was also analyzed. The degree of liver fibrosis was assessed histologically and morphometrically. Results: Plasma transforming growth factor-β1 levels were significantly correlated with transforming growth factor-β1 content in liver tissue ( r=0.83, p<0.001), indicating that plasma levels correspond with tissue cytokine. Plasma transforming growth factor-β1 levels in patients (8.1±1.1 ng/ml) before interferon-α therapy were significantly higher than in controls (1.9±0.3 ng/ml) ( p<0.01). Plasma levels were significantly correlated with the degree of fibrosis ( p<0.01). Plasma transforming growth factor-β1 levels were significantly decreased in sustained responders (from 5.2±1.0 ng/ml to 2.9±0.7 ng/ml), relapsed patients (from 9.8±2.0 ng/ml to 3.4±0.6 ng/ml), and nonresponders (from 9.3±2.1 ng/ml to 3.9±0.9 ng/ml) at the end of therapy ( p<0.05 for all comparisons). Significant regression of liver fibrosis after therapy was observed in both sustained responders and nonresponders ( p<0.05 for both). Conclusions: These observations suggest that plasma transforming growth factor-β1 levels appear to be associated with the degree of liver fibrosis.

Plasma transforming growth factor β1 as a predictor of radiation pneumonitis

Purpose: To investigate prospectively the utility of plasma transforming growth factor β1 (TGFβ1) as a marker for the development of symptomatic radiation pneumonitis. Materials and Methods: Seventy-three patients with lung cancer treated with curative intent are reported herein. Plasma TGFβ1 samples were obtained before, weekly during, and at each follow-up after radiation therapy (RT). TGFβ1 was extracted using an acid/ethanol method. An enzyme-linked immunosorbent assay was used to quantify plasma TGFβ1 concentrations. The TGFβ1 level at the end of RT was considered “normal” if it was both ≤ 7.5 ng/ml and less than the pretreatment value. All patients were followed for at least 6 months, unless symptomatic pneumonitis developed sooner. Pneumonitis was defined by National Cancer Institute (NCI) common toxicity criteria. Results: Fifteen of the 73 patients (21%) developed symptomatic pneumonitis and the remaining 58 (79%) did not. A normal plasma TGFβ1 by the end of RT, as defined above, was more common in patients who did not develop pneumonitis. A return of the plasma TGFβ1 to normal accurately identified patients who would not develop pneumonitis with both a sensitivity and positive predictive value of 90%. Conclusion: Plasma TGFβ1 levels appear to be a useful means to identify patients at low risk for the development of pneumonitis from thoracic RT. Thus, monitoring of plasma TGFβ1 levels may identify candidates for dose escalation studies in the treatment of lung cancer.

124 Plasma transforming growth factor β1 as a predictor of radiation pneumonitis

124 Plasma transforming growth factor β1 as a predictor of radiation pneumonitis

Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis

Purpose : To determine whether changes in the plasma Transforming Growth Factor β1 (TGFβ1) concentration during radiotherapy could identify patients at risk for developing symptomatic radiation pneumonitis. Methods and Materials : Thirty-six patients who received radiation therapy with curative intent for lung cancer ( n = 31), Hodgkin's disease ( n = 4), or thymoma ( n = 1) were evaluated prospectively. All patients had serial plasma TGFβ1 measurements obtained before, during, and after treatment. Plasma TGFβ1 was quantified using an enzyme-linked immunosorbent assay. Pneumonitis were defined clinically. Plasma TGFβ1 levels were considered to have normalized if the following occurred: the last on-treatment TGFβ1 level was both <7.5 ng/ml and lower than the pretreatment level. Results : Thirteen of these 36 patients developed pneumonitis. Significant changes in plasma TGFβ1 levels during treatment were seen only in the subset of patients whose TGFβ1 levels are >7.5 ng/ml at baseline n = 22). Failure of plasma TGFβ1 to normalize by the end of treatment, as defined above, much more accurately identified patients at risk for symptomatic pneumonitis if their baseline TGFβ1 was >7.5 ng/ml than if it was <7.5 ng/ml. Conclusions : Changes in plasma TGFβ1 levels during radiotherapy appars to be a useful means by which to identify patients at risk for the development of symptomatic radiation pneumonitis, particularly in the subset of patients whose pretreatment TGFβ1 levels are >7.5 ng/ml.

Plasma transforming growth factor-β1 reflects disease status in patients with lung cancer after radiotherapy: a possible tumor marker

Purpose: To determine the frequency with which elevated plasma transforming growth factor-β1 (TGFβ1) concentrations occur in lung cancer patients, to determine the kinetics of TGFβ1 expression during and after radiotherapy and to correlate plasma TGFβ1 levels with disease status after treatment. Materials and methods: Plasma samples were obtained before, during and after radiotherapy in 54 patients with lung cancer and 20 normal controls. Plasma TGFβ1 levels were measured using an enzyme-linked immunosorbent assay. Results: Baseline TGFβ1 levels in lung cancer patients and normal controls were 13.0 ± 2.5 and 4.4 ± 0.3 ng/ml, respectively. Elevated TGFβ1 were found in 50% ( 27 54 ) of lung cancer patients. During radiation therapy plasma TGFβ1 levels declined, however, by the completion of treatment the mean TGFβ1 level had not normalized in patients with lung cancer. The TGFβ1 level at last follow-up correlated with disease status in those patients with an increased pretreatment plasma level. Three of four patients with no evidence of cancer had normal follow-up TGFβ1 levels, compared to 2 16 patients with residual or recurrent tumor ( P = 0.02). Conclusions: Elevated plasma TGFβ1 levels occur frequently in patients with lung cancer. In those patients with an elevated plasma TGFβ1 level at diagnosis, monitoring this level may be useful in detecting both disease persistence and recurrence after therapy.

Localization of seminal plasma transforming growth factor-β1 on human spermatozoa: an immunocytochemical study

To localize immunocytochemically transforming growth factor beta1 (TGF-beta1) in human spermatozoa. Incubation of spermatozoa with anti-TGF-beta1 antiserum at various pH. Human volunteers in an academic research institute. Young healthy fertile men. Semen specimens were collected. At neutral pH and at physiological pH of seminal plasma, TGF-beta1 immunostaining was detected predominantly at the postacrosomal region of the head, at the neck, and at the middle piece of the tail. Transforming growth factor-beta1 also was found occasionally at the axial filament complex of the connecting piece and the ring. The acrosomal cap section of the head, the principal piece, or the end piece of the tail were immunocytochemically negative for TGF-beta1. The TGF-beta1 immunostaining pattern at acidic pH was similar to that at neutral pH and at physiological pH of seminal plasma, but a greater intensity of immunostaining was found at acidic pH than that at neutral pH. These results suggest that an in vivo activation of seminal plasma latent TGF-beta1 may take place in the acidic environment of vagina, which results in a greater amount of activated TGF-beta1 and, in turn, with an enhanced "coating" of TGF-beta1 to spermatozoa.

Plasma transforming growth factor-β (TGF-β) levels in hepatic fibrosis: [formula omitted] Duke University Medical Center, Durham, NC, Department of Medicine, ∗Department of Pathology, #Department of Radiation Oncology

Plasma transforming growth factor-β (TGF-β) levels in hepatic fibrosis: [formula omitted] Duke University Medical Center, Durham, NC, Department of Medicine, ∗Department of Pathology, #Department of Radiation Oncology

Prognostic significance of plasma transforming growth factor-β1 levels in patients with hepatocellular carcinoma

Prognostic significance of plasma transforming growth factor-β1 levels in patients with hepatocellular carcinoma

Elevated Plasma Transforming Growth Factor-β1 Levels in Breast Cancer Patients Decrease After Surgical Removal of the Tumor

The authors determined whether untreated breast cancer patients have elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1). Increased plasma TGF-beta 1 levels recently were found after chemotherapy in patients with advanced breast cancer. However, it currently is unknown whether this elevation in plasma TGF-beta 1 is caused by chemotherapy-induced normal tissue damage or whether it results from the presence of the tumor. An enzyme-linked immunosorbent assay was used to measure plasma TGF-beta 1 levels in 26 newly diagnosed breast cancer patients before and after definitive surgery. Patients were grouped by postoperative tumor status: 1) negative lymph nodes (group 1); 2) positive lymph nodes (group 2); and 3) overt residual disease (group 3). The site of TGF-beta 1 production in the tumors was localized by immunohistochemistry and in situ hybridization. Plasma TGF-beta 1 levels were elevated preoperatively in 81% of the patients; TGF-beta 2 and TGF-beta 3 were undetectable. The preoperative TGF-beta 1 levels in the three patient groups were similar; however, the postoperative plasma TGF-beta 1 levels differed by disease status. The mean plasma TGF-beta 1 level in group 1 (n = 12) normalized after surgery (19.3 +/- 3.2 vs. 5.5 +/- 1.0 ng/mL, p < 0.001). In contrast, the mean plasma TGF-beta 1 levels remained above normal in both group 2 (n = 9) and group 3 (n = 5) after surgery. Transforming growth factor-beta 1 expression was found to be preferentially increased in the tumor stroma. Breast tumors result in increased plasma TGF-beta 1 levels in 81% of patients. After surgical removal of the primary tumor, the plasma TGF-beta 1 level normalizes in the majority of patients; persistently elevated levels correlate with the presence of lymph node metastases or overt residual tumor. These findings suggest that the usefulness of TGF-beta 1 as a potential plasma marker for breast tumors deserves further study.

Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma

Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma

Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma

Transforming growth factor-β1 (TGF-β1) has been implicated in tumor progression by promoting angiogenesis or suppressing immune system. We reported previously that transforming growth factor-β1 (TGF-β1) is overproduced by human hepatocellular carcinoma (HCC) tissues and that plasma TGF-β1 levels are elevated in patients with HCC. In the present study, we investigated the relationship between plasma TGF-β1 levels and tumor vascularity as assessed by conventional celiac angiography in 17 patients with HCC. The plasma TGF-β1 level did not correlate with tumor size or underlying liver disease. However, we found that plasma TGF-β1 levels correlated positively with the tumor vascularity. These results suggest that excessive TGF-β1 production may contribute to tumor angiogenesis in HCC.

Changes in plasma TGFβ levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis

Purpose : To determine whether plasma transforming growth factor-β (TGF-β) levels measured before and during radical radiotherapy for lung cancer could be used to predict patients at risk for the development of radiation pneumonitis. Methods and Materials : The first eight patients with lung cancer (nonsmall cell: seven, small cell: one) enrolled in a prospective study designed to evaluate physiological and molecular biologic correlates of radiation induced normal tissue injury are described. The study began in June 1991. All patients were treated with radiotherapy with curative intent. Plasma transforming growth factor-R levels were obtained before, weekly during, and at each follow-up after treatment. Pretreatment pulmonary function tests and single photon emission computed tomography scans were obtained to assess baseline lung function and were repeated at follow-up visits. Dose-volume histogram analyses were performed to determine the volume of lung which received ≥ 30 Gy. Patients were assessed at each follow-up visit for signs and symptoms of pneumonitis. Results : Five patients developed signs and/or symptoms of pulmonary injury consistent with pneumonitis and three patients did not. In all three patients not developing pneumonitis, plasma TGF-β levels normalized by the end of radiotherapy. In contrast, four out of five patients who suffered pneumonitis had persistently elevated plasma TGF-β levels by the end of therapy. This finding appeared to be independent of the volume of irradiated lung. Conclusions : These results suggest that plasma TGF-β levels during treatment may be useful to determine which patients are at high risk of developing symptomatic pneumonitis following thoracic radiotherapy. This finding may have implications when planning additional therapy (either chemotherapy or radiotherapy) which may have potentially adverse consequences on the lung.