Age-Related Changes of Transforming Growth Factor β1 in Japanese Children

BackgroundTransforming growth factor β1 (TGFβ1) is an important factor in immunomodulation. The expression of TGFβ1 has been shown to be influenced by the C-509 T polymorphism in the TGFβ1 gene. We investigated age-related changes of plasma TGFβ1 levels in a birth-cohort study. In addition, the genotypes of the C-509 T polymorphism were investigated in allergic and non-allergic subjects.MethodsSixty-four neonates who met the following criteria were enrolled in this cohort study: 1) full-term vaginally delivery; 2) underwent DNA polymorphism analysis; and 3) questionnaire forms were filled out by parents at 0, 6 and 14 months of age. The umbilical cord blood at 0 months and peripheral blood at 6, and 14 months were collected. Plasma TGFβ1 levels were measured at 0, 6 and 14 months of age. Genomic DNA was extracted from their umbilical cord blood. The genotype of the subjects was examined for the presence of C- 509 T.ResultsThe plasma TGFβ1 level at 6 months was the highest of the 3 measurements (at 0, 6, and 14 months of age). The TGFβ1 levels at 14 months in allergic subjects were significantly higher than those in non-allergic subjects (p = 0.03). All subjects with bronchial asthma (n = 3) had the TT genotype of the C-509 T polymorphism.ConclusionsThe plasma TGFβ1 levels change with age. In addition, TGFβ1 may play a role in the pathogenesis of bronchial asthma.     

Transforming Growth Factor β1 and Coronary Intimal Hyperplasia in Pediatric Patients With Congenital Heart Disease

Background

Congenital heart defects or the process of their repair leads to an increased risk for adult cardiovascular disease compared with the general population. Intimal hyperplasia is a preatherosclerotic lesion that may be produced as a consequence of transforming growth factor β1 (TGF-β1) pathway activation. We studied the presence of intimal hyperplasia in arteries from a pediatric population with congenital heart disease (CHD) and TGF-β1 expression to enlighten its possible role in the genesis of these lesions.

Methods

Coronary arteries from 10 controls and 98 CHD patients (54% cyanotic type, 32% surgically repaired) were stained, and the presence and degree of intimal thickening were analyzed. The expression of TGF-β1 was studied by immunohistochemistry.

Results

The difference between the presence of coronary intimal hyperplasia in patients with cyanotic (35; 66.1%) and noncyanotic CHD (29; 64.3%) was not significant. However, surgically repaired CHD presented a higher rate of coronary intimal hyperplasia (80%) than did the group without surgical intervention (47.3%), P = 0.0002. The immunostaining for TGF-β1 analyzed in samples of patients with cyanotic and noncyanotic CHD showed no significant differences. However, TGF-β1 expression was more intense on the intimal layer of patients with surgically repaired CHD than on that of those without surgery (intimal area positive for TGF-β1, 50.43% vs 15.91%, respectively; Mann-Whitney U test P = 0.0005).

Conclusion

The high incidence of intimal hyperplasia in patients with surgically repaired CHD is correlated with TGF-β1 expression and may contribute to the development of atherosclerotic coronary artery disease in CHD patients.     

Immunolocalization of Transforming Growth Factor-α and Epidermal Growth Factor Receptor in the Rat Gastroduodenal Area

The maintenance of gastrointestinal epitheliumintegrity requires a fine balance between proliferationand differentiation as well as protection againstgastric acid secretion. Transforming growthfactor- (TGF-) regulates these functions bybinding to epidermal growth factor receptor (EGF-R).This study was designed to identify the localization ofTGF- and EGF-R in the rat gastroduodenal region. In the stomach, the surface and gastric pitcells showed staining for TGF- antibodies in thecytoplasm and basolateral and apical membranes.TGF- and EGF-R were observed in the supranuclearregion of the cells lining the gland. In the duodenum,the enterocytes coexpressed both TGF- and EGF-Rin the supranuclear area. The EGF-R was also observed inthe apical membrane. Brunner's glands were positive for both TGF- and EGF-R antibodies. Ourresults demonstrate the coexpression of TGF- andEGF-R in the rat gastroduodenal area, which suggests afunctional role for them in the establishment and maintenance of the epithelialrenewal.     

Enhanced Expression of Transforming Growth Factor (TGF) -α Precursor and TGF-β1 During Paneth Cell Regeneration

An intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, induces selective killing and rapid regeneration of Paneth cells, which have a large amount of zinc in their cytoplasmic granules. We examined the expression pattern of transforming growth factor (TGF) - and TGF-₁ in this regenerative process. Messenger RNA expression of TGF- and TGF-₁ reached their peaks at 12 and 24 hr after dithizone injection, respectively. Protein expression of TGF- precursor and TGF-₁ increased to a maximum at 24 and 72 hr, respectively. Their immunoreactivities were localized in the epithelial cells in the vicinity of Paneth cells, whereas they were prominent in the upper half of the crypts in control rats. In conclusion, destruction of Paneth cells induced TGF- precursor expression, followed by an increase of TGF-₁ especially in the crypt bases. This unique expression pattern of two growth factors may be involved in rapid regeneration of Paneth cells.     

Cyclic Platelet and Leukocyte Count Oscillation in Chronic Myelocytic Leukemia Regulated by the Negative Feedback of Transforming Growth Factor β

We report a case of chronic myelocytic leukemia (CML) with cyclic oscillation of platelet and leukocyte counts and attempt to elucidate the oscillatory mechanism from the standpoint of cytokine regulation of hematopoiesis. A 57-year-old woman with a diagnosis of CML exhibited platelet and white blood cell (WBC) count fluctuations of a cyclic nature. The average duration of the cycles was about 8 weeks. The patient suffered from headache, fatigue, and malaise at the peak of the cycle. The peak thrombopoietin concentration in peripheral blood coincided with a period of decrease in platelet numbers. The change in transforming growth factor beta (TGF-beta) level paralleled that of the platelet numbers. A progenitor cell assay revealed the suppression of trilineage colony formation in the presence of plasma from the blood cell peak point, and this suppression was completely blocked when the plasma was incubated with an anti-TGF-beta antibody. From these findings, we concluded that the cyclic oscillation of the platelet, WBC, and reticulocyte counts had been induced by excess negative feedback to megakaryopoiesis by TGF-beta.     

Transforming Growth Factor β, Pleiotropic Regulator of Hematopoietic Stem Cells: Potential Physiological and Clinical Relevance

Transforming growth factor beta (TGF-beta) is a pleiotropic regulator of all stages of hematopoieis. Depending on the differentiation stage of the target cell, the local environment, and the concentration of TGF-beta, TGF-beta can be proproliferative or antiproliferative, proapoptotic or antiapoptotic, and/or prodifferentiative or antidifferentiative. TGF-beta is the major regulator of stem cell quiescence and can act directly or indirectly through effects on the marrow microenvironment. In addition, paracrine and autocrine actions of TGF-beta have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Neutralization of autocrine TGF-beta has therapeutic potential.     

Increased Expression of Transforming Growth Factor-β1 During Gastric Ulcer Healing in Rats

This study was done to investigate theexpression and localization of transforming growthfactor-₁ (TGF-₁) inthe gastric ulcerated tissues produced by acetic-acidduring the healing process, by northern blot analysis and immunohistochemicaltechnique. Ulcerated TGF-₁ mRNA levelswere significantly increased from days 3 to 18, in asimilar manner to extracellular matrix proteins, andreturned to control levels at the scarred phase.Immunoreactive TGF-₁ was localized inepithelial cells beneath proliferative zone in intacttissues. 1 In ulcerated tissues, TGF-₁was localized in macrophages in the ulcer bed and in fibroblasts ormyofibroblasts in the granulation tissues. Treatmentwith prostaglandin E₁ (PGE₁)further stimulated ulcerated TGF-₁expression, being associated with the acceleration of gastric ulcer healing, while treatment withindomethacin reduced TGF-₁ expression,being accompanied by the delayed ulcer healing. Thecombination of PGE₁ and indomethacin reversedthe indomethacin-induced decrease in ulcerated TGF-₁.Thus, TGF-₁ may be implicated in theacceleration of gastric ulcer healing.     

Maternal Serum Levels of Transforming Growth Factor ß1 (TGF-ß1) in Normal and Preeclamptic Pregnancies

Background: Successful pregnancy in allopregnant women depends upon the control of graft rejection mechanisms. It has been suggested that some immunosuppressive cytokines contribute to successful pregnancy and transplantation. Transforming growth factor beta (TGF-   β) exhibits potent immunoregulatory and anti-inflammatory properties which might prolong graft survival. Recent studies suggest a role for TGF- β   in the generation of T-regulatory lymphocytes which preserves the tolerance to peripheral self antigens and may control the response to allogenic tissues and thereby promote the transplantation tolerance. Also, the function of TGF-   β in trophoblast differentiation and hypertension is reported.   Objective: To evaluate the maternal serum TGF-   β1 level in normal allopregnant women and in pregnancies complicated by preeclampcia (PE).   Methods: Sixty one pregnant preeclamptic women (32 cases with severe and 29 with mild PE), 22 normotensive healthy pregnant, and 20 non-pregnant controls constituted the studied groups. The active form of TGF-   β1 in serum from all cases was investigated by indirect ELISA technique.   Results: The results showed that TGF-   β1 level was higher in all three pregnant groups as compared with the nonpregnant controls. No significant changes in serum levels of TGF-   β1 were found in PE as compared with the normal pregnancy.   Conclusion: TGF-β1 may function as a regulatory factor in fetal allograft survival during pregnancy, and TGF-   β1 does not have a pathophysiological role in PE.     

Does the Expression of Transforming Growth Factor β-1: Affect the Outcome of the Radiofrequency Modified Maze Procedure in Patients with Rheumatic Atrial Fibrillation?

We investigated whether the expression of transforming growth factor β-1 in the left atrial appendage affected the outcome of the radiofrequency modified maze procedure in patients with rheumatic valve disease and long-standing persistent atrial fibrillation.Messenger RNA and protein expression of transforming growth factor β-1 and volume fractions of collagen types I and III were measured in 80 patients with rheumatic valve atrial fibrillation who underwent valve surgery with the radiofrequency modified maze procedure; the same was done in a control group of 20 patients with rheumatic valve disease and sinus rhythm who underwent valve surgery alone.At 6 months' follow-up, atrial fibrillation recurred in 24 of the 80 patients in the study group. The messenger RNA and protein expressions of transforming growth factor β-1, collagen type I volume fraction, and left atrial dimension had increased gradually in the control group and in the study subgroups that maintained sinus rhythm or relapsed into atrial fibrillation (P <0.05). The messenger RNA and protein expressions of transforming growth factor β-1 correlated positively with collagen type I volume fraction (r=0.723, P <0.001 and r=0.745, P <0.001, respectively) and left atrial dimension (r=0.762, P <0.001 and r=0.765, P <0.001, respectively). In the sinus rhythm-maintained subgroup, the patients who regained functional atrial contraction had lower messenger RNA and protein expression of transforming growth factor β-1 than did the patients who failed to retain such function (P <0.05).We conclude that the expression of transforming growth factor β-1 in the resected left atrial appendage affects the recurrence of atrial fibrillation and restoration of functional left atrial contraction after the radiofrequency modified maze procedure.     

High-Expression of Transforming Growth Factor β1 and Phosphorylation of Extracellular Signal-Regulated Protein Kinase in Vascular Smooth Muscle Cells from Aorta and Renal Arterioles of Spontaneous Hypertension Rats

To further elucidate the molecular mechanisms involved in hypertensive vascular remodeling, an immunohistochemical technique and Western blot were applied to study phospho-extracellular signal-regulated kinase (ERK1/2) and transforming growth factor β₁ (TGF-β₁) expression in endothelial and vascular smooth muscle cell (VSMC) of the thoracic aorta and renal arterioles from SHR of different ages. Results of both the immunohistochemistry and Western blot assays showed that either the phospho-ERK1/2 at endothelium or VSMC of renal small arteries from SHR8, SHR16, and SHR20 groups and of the aorta from SHR16 and SHR20 were higher than that from control group. Comparing with that in the small arteries of the kidney, the phospho-ERK1/2 in the endothelium and in VSMC was markedly increased in the aorta, and high expression of TGF-β1 was detected in the aorta and kidney from SHR16 and SHR20 by Western blot. These results suggested that ERK 1/2 could be activated by phosphorylation with over-expression of TGF-β₁ in the endothelium and in VSMC of aorta and renal arterioles from SHR, which might play an important role in VSMC proliferation under hypertension.     

Bronchial Asthma Showing Reduction in FEV1 after Inhalation of Qvar™

The administration of Qvar (a hydrofluoroalkane-134a beclomethasone dipropionate; HFA-BDP) is highly useful for the treatment of patients with asthma. However, we found in a case of bronchial asthma that replacing the prior inhaled corticosteroids with Qvar resulted in temporary dyspnea and reduction in forced expiratory volume in 1 second (FEV₁). Qvar contains beclomethasone dipropionate combined with absolute ethanol and an alternative to fluorocarbon. The patient had complicated alcohol-induced asthma. FEV₁ decreased markedly and immediately after Qvar inhalation. The Qvar placebo is free of beclomethasone but contains other ingredients (ethanol and fluorocarbon). FEV₁ did not decrease after the Qvar placebo, Aldecin inhalation, and Qvar inhalation orally treated with atropine before inhalation of Qvar?. It seems unlikely that the components of Qvar (except beclomethasone) are responsible for the reduction in FEV₁ observed immediately after inhalation of Qvar. These findings would be noteworthy when using Qvar for Japanese patients with asthma known to have a relatively high frequency of the complication of alcohol-induced asthma.     

Expression of Transforming Growth Factor-α and -β in Hepatic Lobes After Hemihepatic Portal Vein Embolization

Hemihepatic portal vein embolization (PVE) concomitantly induces atrophy in embolized and compensatory hypertrophy in nonembolized hepatic lobes. The aim of the present study was to evaluate the involvement of growth stimulatory and inhibitory factors in these hepatic lobes after PVE. Liver specimens from the embolized and nonembolized lobes of ten patients who underwent hepatectomy (8–22 days) after undergoing PVE were obtained. Proliferation and apoptosis were examined immunohistochemically using Ki-67 and the Tdt-mediated dUTP-biotin nick end-labeling method. The expression of transforming growth factor-α (TGF-α) and transforming growth factor-β (TGF-β) was also examined by immunohistochemical staining. PVE induced hepatocyte apoptosis in the embolized lobe and hepatocyte proliferation in the nonembolized lobe. TGF-α expression in the hepatocytes of the nonembolized lobe was markedly increased, whereas TGF-α was also overexpressed, albeit moderately, in the embolized lobe. In contrast, TGF-β expression in the hepatocytes of the embolized lobe was significantly increased, and TGF-β expression was also increased, although to a lesser extent, in the nonembolized lobe. The degree of volume changes of the nonembolized lobe and the embolized lobe after PVE was statistically correlated with the ratios of TGF-α and TGF-β expression in these lobes (r = 0.886, P < .0001). In conclusion, these findings indicate that TGF-α and TGF-β expression (assessed by immunohistochemical staining) increase in relation to hepatocyte proliferation and apoptosis, respectively, after PVE in humans and the balance of the two factors may contribute to hepatic atrophy and hypertrophy concomitantly observed in this model.