Histological and Biochemical Evaluation of Urethral Scar following Three Different Hypospadias Repairs: An Experimental Study in Rabbits

2017 ◽  
Vol 28 (05) ◽  
pp. 420-425 ◽  
Author(s):  
Xiao-Hui Tan ◽  
Chun-Lan Long ◽  
De-Ying Zhang ◽  
Tao Lin ◽  
Da-Wei He ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
White Male ◽  
Transforming Growth Factor Β1 ◽  
Rational Approach ◽  
Hypospadias Repair ◽  
Tubularized Incised Plate ◽  
Biochemical Evaluation ◽  
Tubularized Incised Plate Urethroplasty ◽  
Tgf Β1

Introduction Several urethroplasties have been employed in the surgical treatment of hypospadias. Neourethral strictures are among the most common postoperative complications that often require reoperation. Materials and Methods We created a hypospadias model in New Zealand white male rabbits through a hypospadias-like defect and acute repair. A total of 24 animals were randomly allocated into three groups: tubularized incised-plate urethroplasty (TIPU) group (8), perimeatal-based flap urethroplasty (Mathieu) group (8), onlay island flap urethroplasty (onlay) group (8), and corresponding surgical procedures were immediately performed to reconstruct neourethra. The rabbits were killed postoperatively at 5 days, 2 weeks, 6 weeks, and 3 months, respectively. The penile tissue was harvested for histological and biochemical investigations to evaluate the expressions of transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMactin) in all groups. Results All rabbits were operated on uneventfully. The amount of collagen content was increased in the Mathieu and onlay groups than in the TIPU group (p < 0.05). Biochemical analysis showed that the expression of TGF-β1 in the TIPU group was decreased compared with the two other groups at 2 or 6 weeks postoperatively (p < 0.01). The expression pattern regarding α-SMactin was similar at 6 weeks or 3 months postoperatively (p < 0.01). Conclusion The neourethra repaired by TIPU was practically resumed to normal anatomy and scarring was less apparent than the two other groups. Therefore, TIPU is considered as a relatively rational approach for hypospadias repair. The activity of fibroblasts has been increased in the long term, which may be the pathogenesis of neourethral stricture following hypospadias repair.

Abstract 3054: Comparison of Transforming Growth Factor-β1 Expression in Aortic Wall of Thoracic Aortic Aneurysm Versus Dissection

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shouguo Yang ◽  
Guanggen Cui ◽  
Ramin Beygui ◽  
Fardad Esmailian ◽  
Abbas Ardehali ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Wall ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Transforming Growth Factor Β1 ◽  
Fluorescent Intensity ◽  
Nucleus Density ◽  
Tgf Β1

Background The underlying mechanism of thoracic aortic aneurysm (TAA) and dissection(TAD) was undetermined, and one controversy lies in whether they represent the different dvelopement period of the same disorder or totally diferent diseases. This study is in aim to compare the expression and distribution of Transforming Growth Factors(TGF) β1 in the aortic wall of TAA versus TAD patients. Method Aortic specimens were obtained from patients underwent to aortic procedures for TAA (n=38) and TAD (n=20) at UCLA , and control aorta (CN) from organ donnor (n=20). Double immunofluorescent stainning of TGF-β1 and α-smooth muscle actin were performed with paraffin embeded slides for all aortic samples and semiquantified by fluorescent intensity analysis. Histopathologic examination were performed with HE, Verhoeff van-Gieson and Masson’s trichrome stain. Results TAA and TAD patients exhibited an up-regulation of TGF-β1 to 120.3% and 109.6% compared with CN separately (P<0.05), with TAA higher than TAD (P<0.05). TGF-β1 distributed unevenly across aortic wall with the highest levels expression in tunica media, followed by intima then adventitia. In intima, TGF-β1 was expressed at the same level for TAD as CN, but was increased to 115.2% for TAA compared to CN (P<0.05). In media, TGF-β1 increased by 127.2% in TAA and 116.1% in TAD compared to CN (P<0.01), with TAA being higher than TAD (P<0.05). In adventitia, TGF- β1 was up-regulated to 119.6% and 116.7% for TAA and TAD compared to CN (P<0.05). Nucleus density analysis showed cellular plasia in adventitia of TAA and TAD than CN (P<0.05 ), while TAD patients demonstrated a higher nucleus density than TAA in intima and adventitia (P<0.05). α-actin was increased in media of TAA and TAD to 164.5% and 120% than CN (P<0.01 and P<0.05). Attenuated and interrupted elastin and mild to severe cystic medial degeneration were characteristic histopathologic finding in 29 (76.3%) TAA and 17(85%) TAD patients. Conclusions TGF- β1 expression was up-regulated in aortic wall of TAA and TAD compared to CN. The significant higher levels of TGF- β1 in intima and media in TAA versus TAD patients implicated a probable positive effect of TGF- β1 to maintain aortic wall integrity, and/or greater comsamption of TGF- β1 in the aortic dissection.

scholarly journals The Role of Myofibroblasts in Granulomatous Lymphadenitis in Pigs Naturally Infected with M. Avium Subsp. Hominissuis

2018 ◽  
Vol 41 (1) ◽  
pp. 47-53
Author(s):  
Vladimir Polaček ◽  
Dejan Vidanović ◽  
Biljana Božić ◽  
Žolt Beckei ◽  
Ivana Vučićević ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Natural Infection ◽  
Interferon Γ ◽  
Transforming Growth Factor Β1 ◽  
Positive Tuberculin Skin Test ◽  
Type I ◽  
A Genome ◽  
Granulomatous Lymphadenitis ◽  
Tgf Β1

Abstract The most important morphological characteristic of infections caused by M. avium subsp. hominissuis (MAH) is granuloma formation. The growth of mycobacteria is in accordance with anti-bacterial effector mechanisms of the host within granuloma. The most important cytokines for „orchestrating“the host defense are interferon γ (INF-γ), tumor necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1). Myofibroblasts that make up a peripheral layer of granuloma largely express receptors for TGF-β1. This cytokine is believed to affect the induction of myofibroblast proliferation. The aim of this paper is to point out the importance of myofibroblasts in the formation and sustainability of granuloma during natural infection of pigs with M. avium subsp. hominissuis. Examinations have been performed on the samples of Lnn. jejunales, Lnn. ileocolici and Lnn. colici of 100 pigs with a positive tuberculin skin test. The molecular method confirmed the presence of a genome M. avium subsp. hominissuis. The microscopic examination of lymph node samples stained by the routine hematoxyilin-eosin (HE) method, showed the presence of granulomatous lymphadenitis. The method of double immunohistochemical staining revealed that myofibroblasts which express TGF-β1 receptor type I (TGF-β1RI) and α smooth muscle actin (α SMA) have an important role in the morphogenesis of granulomatous lymphadenitis in pigs infected with MAH.

scholarly journals Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-β1/Smads Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenxuan Jiao ◽  
Man Bai ◽  
Hanwei Yin ◽  
Jiayi Liu ◽  
Jing Sun ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Thioredoxin Reductase ◽  
Transforming Growth Factor Β1 ◽  
Therapeutic Effects ◽  
Pathological State ◽  
Tgf Β1

Liver fibrosis is an important stage in the progression of liver injury into cirrhosis or even liver cancer. Hepatic stellate cells (HSCs) are induced by transforming growth factor-β1 (TGF-β1) to produce α-smooth muscle actin (α-SMA) and collagens in liver fibrosis. Butaselen (BS), which was previously synthesized by our group, is an organic selenium compound that exerts antioxidant and tumor cell apoptosis–promoting effects by inhibiting the thioredoxin (Trx)/thioredoxin reductase (TrxR) system. The aim of this study was to investigate the potential effects of BS on liver fibrosis and explore the underlying molecular mechanisms of its action. Liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. BS was administered orally once daily at a dose of 36, 90, or 180 mg/kg. Silymarin (Si), which is a drug used for patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, was administered at a dose of 30 mg/kg per day as a control. The action mechanisms of BS against liver fibrosis progression were examined in HSCs. The study revealed that the activity and expression levels of TrxR were elevated in the mouse liver and serum after CCl4-induced liver fibrosis. Oral administration of BS relieved the pathological state of mice with liver fibrosis, showing significant therapeutic effects against liver fibrosis. Moreover, BS not only induced HSC apoptosis but also inhibited the production of α-SMA and collagens by HSCs by downregulating the TGF-β1 expression and blocking the TGF-β1/Smads pathway. The results of the study indicated that BS inhibited liver fibrosis by regulating the TGF-β1/Smads pathway.

scholarly journals Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

2018 ◽  
Vol 132 (21) ◽  
pp. 2299-2322 ◽  
Author(s):  
Jinfang Bao ◽  
Yingfeng Shi ◽  
Min Tao ◽  
Na Liu ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Growth Factor Receptor ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Renal Tissue ◽  
Tgf Β1

Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction. However, the role and underlying mechanisms of autophagy in hyperuricemic nephropathy (HN) remain unknown. In the present study, we observed that inhibition of autophagy by 3-methyladenine (3-MA) abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1 (TGF-β1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function, preserving renal tissue architecture, reducing the number of autophagic vacuoles, and decreasing microalbuminuria. Moreover, 3-MA was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGF-β1 and TGFβ receptor I, phosphorylation of Smad3 and TGF-β-activated kinase 1 (TAK1), and activation of multiple cell signaling pathways associated with renal fibrogenesis, including Wnt, Notch, EGFR, and nuclear factor-κB (NF-κB). 3-MA treatment remarkably inhibited all these responses. In addition, 3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Collectively, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.

scholarly journals Effect of sex differences in treatment response to angioplasty in a murine arteriovenous fistula model

2020 ◽  
Vol 318 (3) ◽  
pp. F565-F575 ◽  
Author(s):  
Chuanqi Cai ◽  
Chenglei Zhao ◽  
Sreenivasulu Kilari ◽  
Amit Sharma ◽  
Avishek K. Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arteriovenous Fistula ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Neointimal Hyperplasia ◽  
Peak Systolic Velocity ◽  
Transforming Growth Factor Β1 ◽  
Histopathological Analysis ◽  
Intimal Thickening ◽  
Tgf Β1

Failure to mature and venous neointimal hyperplasia formation are the two major causes of hemodialysis arteriovenous fistula (AVF) vascular access failure. Percutaneous transluminal angioplasty (PTA) is the firstline treatment for both of these conditions, but, clinically, women have decreased patency rates compared with men. The hypothesis to be tested in the present study was that female mice after PTA of venous areas of higher intimal thickening have increased gene expression of transforming growth factor-β1 (TGF-β1) and TGF-β receptor 1 (TGFβ-R1) accompanied with histological changes of fibrosis compared with male mice. Seventeen male and eighteen female C57BL/6J mice were used in this study. Chronic kidney disease was induced by partial nephrectomy, and, 28 days later, an AVF was created to connect the left carotid artery to the right jugular vein. Two weeks later, the higher intimal thickening area was treated with PTA, and mice were euthanized 3 days later for gene expression analysis or 14 days later for histopathological analysis. Doppler ultrasound was performed weekly after AVF creation. At day 3, female AVF had significantly higher average gene expression of TGF-β1 and TGFβ-R1 compared with male AVF. At day 14, female outflow veins had a smaller venous diameter, lumen vessel area, decreased wall shear stress, lower average peak systolic velocity, and an increased neointima area-to-media area ratio. Moreover, female outflow veins showed a significant increase in α-smooth muscle actin and fibroblast-specific protein-1. There was a decrease in M1/M2 with an increase in CD68.

scholarly journals Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

2017 ◽  
Vol 313 (4) ◽  
pp. F961-F972 ◽  
Author(s):  
Junpeng Wang ◽  
Yang Chen ◽  
Di Gu ◽  
Guihao Zhang ◽  
Jiawei Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bladder Wall ◽  
Transforming Growth Factor Β1 ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Tgf Β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

scholarly journals Glucosamine impedes transforming growth factor β1-mediated corneal fibroblast differentiation by targeting Krüppel-like factor 4

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Ying-Jen Chen ◽  
Shih-Ming Huang ◽  
Ming-Cheng Tai ◽  
Jiann-Torng Chen ◽  
Chang-Min Liang
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Disease Model ◽  
Immunoblot Analysis ◽  
Transforming Growth Factor Β1 ◽  
Myofibroblast Differentiation ◽  
Alpha Smooth Muscle Actin ◽  
Corneal Fibroblasts ◽  
Tgf Β1

Abstract Background Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. Currently, there are no effective agents targeting TGF-β signaling to diminish corneal fibrosis. Glucosamine (GlcN), which is widely used in the treatment of osteoarthritis, abrogates the morphologic effects of TGF-β2 on retinal pigmented epithelial cells in a mouse disease model. Here, we sought to determine whether GlcN would exert beneficial effects against TGF-β1-induced corneal fibrosis. Methods In human corneal fibroblasts (HCFs) treated with GlcN, the expression of Krüppel-like factor 4 (KLF4) and its downstream signaling effects were determined in the presence and absence of TGF-β1 using immunoblot analysis. We further explored GlcN inhibition of fibroblast-to-myofibroblast differentiation via KLF4 siRNA. The effect of cycloheximide on KLF4 protein levels with or without GlcN administration was assessed to determine whether GlcN affects the stability of the KLF4 protein. Results In HCFs, GlcN induced the expression of KLF4, which regulated the maturation and maintenance of the ocular surface. GlcN partially suppressed the TGF-β1-induced expression of alpha-smooth muscle actin (α-SMA) and reduced the collagen contraction capacity in HCFs, suggesting a decrease in fibroblast-to-myofibroblast differentiation. This effect appeared to be mediated through suppression of Smad2 phosphorylation and ERK-dependent signaling. The levels of KLF4 mRNA were increased by GlcN and decreased by TGF-β1 and the TGF-β1-induced α-SMA mRNA expression was upregulated when the KLF4 gene was silenced. GlcN also appeared to stabilize the KLF4 protein, reducing its turnover in corneal fibroblasts. Conclusion These findings shed light on a novel mechanism by which GlcN suppresses TGF-β1-induced fibroblast-to-myofibroblast differentiation through the upregulation of KLF4 expression. Current strategies for treating corneal fibrosis were not effective. Elevating KLF4 levels through the use of GlcN might provide an effective alternative to alleviate the development and progression of corneal fibrosis.

α-Lipoic acid modulates liver fibrosis: A cross talk between TGF-β1, autophagy, and apoptosis

2019 ◽  
Vol 39 (4) ◽  
pp. 440-450 ◽  
Author(s):  
WH El-Maadawy ◽  
OA Hammam ◽  
SH Seif el-Din ◽  
NM El-Lakkany
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Lipoic Acid ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Alpha Smooth Muscle Actin ◽  
Tgf Β1

Autophagy and apoptosis are important players in the progression of hepatic fibrosis via activation of hepatic stellate cells (HSCs). Despite the recently depicted antifibrotic effects of alpha-lipoic acid (ALA), however, its modulatory effects on HSCs autophagy remain unverified. Our study aimed to elucidate the underlying antifibrotic mechanisms through which ALA mediates HSC autophagy and apoptosis. Liver fibrosis was induced via thioacetamide (TAA) intoxication in rats; TAA-intoxicated rats were treated with either silymarin or ALA. Effect of ALA on biochemical parameters and immunohistopathological examinations was measured and compared to silymarin. ALA restored normal hepatic architecture (S1 vs. S4), liver functions, hepatic glutathione, and transforming growth factor-β1 levels. ALA ameliorated hepatic levels of malondialdehyde, platelet-derived growth factor, tissue inhibitor metalloproteinases-1, hydroxyproline, and expression of alpha-smooth muscle actin. Moreover, ALA significantly reduced messenger RNA expression of LC3-II genes and triggered caspase-3 expression. Interestingly, ALA exhibited superior activities over silymarin regarding suppression of proliferation, activation and autophagy of HSCs, collagen deposition, and induction of HSCs apoptosis. In conclusion, treatment of TAA-intoxicated rats with ALA inhibited autophagy and induced apoptotic clearance of activated HSCs. Accordingly, this study provides mechanistic insights into the possible applicability of ALA in the treatment of hepatic fibrosis.

scholarly journals SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma

2021 ◽  
Vol 22 (23) ◽  
pp. 12790
Author(s):  
Milena Paw ◽  
Dawid Wnuk ◽  
Kinga Nit ◽  
Sylwia Bobis-Wozowicz ◽  
Rafał Szychowski ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Connexin 43 ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Bronchial Wall ◽  
Asthmatic Patients ◽  
Tgf Β1

Subepithelial fibrosis is a component of the remodeling observed in the bronchial wall of patients diagnosed with asthma. In this process, human bronchial fibroblasts (HBFs) drive the fibroblast-to-myofibroblast transition (FMT) in response to transforming growth factor-β1 (TGF-β1), which activates the canonical Smad-dependent signaling. However, the pleiotropic properties of TGF-β1 also promote the activation of non-canonical signaling pathways which can affect the FMT. In this study we investigated the effect of p38 mitogen-activated protein kinase (MAPK) inhibition by SB203580 on the FMT potential of HBFs derived from asthmatic patients using immunocytofluorescence, real-time PCR and Western blotting methods. Our results demonstrate for the first time the strong effect of p38 MAPK inhibition on the TGF-β1-induced FMT potential throughout the strong attenuation of myofibroblast-related markers: α-smooth muscle actin (α-SMA), collagen I, fibronectin and connexin 43 in HBFs. We suggest the pleiotropic mechanism of SB203580 on FMT impairment in HBF populations by the diminishing of TGF-β/Smad signaling activation and disturbances in the actin cytoskeleton architecture along with the maturation of focal adhesion sites. These observations justify future research on the role of p38 kinase in FMT efficiency and bronchial wall remodeling in asthma.

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