887 Integrated Pathways of Fibrogenesis in Eosinophilic Esophagitis: Active Secretion of Th2 Cytokines and TGF-β1, and Binding of Activated Eosinophils Promote Collagen I and Fibronectin Production By Human Esophageal Mesenchymal Cells

AbstractThe present study explores the mechanism of resistance to pulmonary fibrosis by observing the possible effects of serum containing drugs prepared from Gua Lou Xie Bai decoction (GLXB-D) on transforming growth factor beta 1 (TGF-β1) induced Epithelial-mesenchymal transition (EMT) of A549 human alveolar epithelial cells. The inhibition rate was observed with the help of thiazolyl blue tetrazolium bromide (MTT) in 24 h and 48 h treated cells. Inverted microscope and transmission electron microscope (TEM) were used to study the changes in the morphology and ultrastructure of the cells. The expressions of E-cadherin and Vimentin were comparatively analyzed by Western blotting, while the expressions of Collagen I and III were analyzed by ELISA. The data obtained indicated that the expression of epithelial marker E-cadherin was decreased, while the expressions of EMT markers such as Vimentin and Collagen I and III were increased in 24 h after TGF-β1 induction. However, the serum containing drugs of GLXB-D were found to inhibit the TGF-β1 induced proliferation of cells, increase the expression of E-cadherin and decrease the expression of Vimentin, collagen I and III. In conclusion, the serum containing drugs of GLXB-D effectively reduced pulmonary fibrosis, mainly via the reversal of EMT induction by TGF-β1. Thus, it can be considered as a potential candidate for the development of better treatment methods for pulmonary fibrosis.

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Post-translational modification of CREB-1 decreases collagen I expression by inhibiting the TGF-β1 signaling pathway in rat hepatic stellate cells

Molecular Medicine Reports ◽

10.3892/mmr.2016.5926 ◽

2016 ◽

Vol 14 (6) ◽

pp. 5751-5759 ◽

Cited By ~ 3

Author(s):

Xiaoling Deng ◽

Liang Deng ◽

Pei Wang ◽

Chunwei Cheng ◽

Keshu Xu

Keyword(s):

Signaling Pathway ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Collagen I ◽

Post Translational Modification ◽

Tgf Β1

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Transplantation of Telocytes Attenuates Unilateral Ureter Obstruction-Induced Renal Fibrosis in Rats

Cellular Physiology and Biochemistry ◽

10.1159/000489445 ◽

2018 ◽

Vol 46 (5) ◽

pp. 2056-2071 ◽

Cited By ~ 3

Author(s):

Long Zheng ◽

Long Li ◽

Guisheng Qi ◽

Mushuang Hu ◽

Chao Hu ◽

...

Keyword(s):

Growth Factor ◽

Protective Effect ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Kidney Tissue ◽

Collagen I ◽

Enzyme Linked Immunosorbent Assay ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Tgf Β1

Background/Aims: Previous studies imply that telocytes may have a protective effect on fibrosis in various organs, including the liver, colon, and heart. The effect of telocytes on renal fibrosis remains unknown. Herein, this study was designed to investigate the effect of telocytes on renal fibrosis and the potential mechanisms involved. Methods: In a unilateral ureteral obstruction (UUO)-induced renal fibrosis model, telocytes were injected via the tail vein every other day for 10 days. The degree of renal damage and fibrosis was determined using histological assessment. The expression of collagen I, fibronectin, epithelial-mesenchymal transition markers, and Smad2/3 phosphorylation was examined by western blot analyses. Real-time PCR and enzyme-linked immunosorbent assay were performed in vivo to detect the levels of transforming growth factor (TGF)-β1 and various growth factors. Results: Telocytes attenuated renal fibrosis, as evidenced by reduced interstitial collagen accumulation, decreased expression of fibronectin and collagen I, upregulation of E-cadherin, and downregulation of α-smooth muscle actin. Furthermore, telocytes decreased serum TGF-β1 levels, suppressed Smad2/3 phosphorylation, and increased the expression of hepatocyte growth factor (HGF) in rat kidney tissue following UUO. Blockage of HGF counteracted the protective effect of telocytes on UUO-treated kidneys. Through the detection of HGF mRNA levels in vitro, we found that telocytes had no effect on HGF expression compared with renal fibroblasts. Conclusion: Telocytes attenuated UUO-induced renal fibrosis in rats, likely through enhancing the expression of HGF in an indirect manner.

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Mo1229 TH2-CYTOKINES SUPRESS CD73-POSITIVE CELL-MEDIATED EPITHELIAL REGENERATION IN EOSINOPHILIC ESOPHAGITIS

Gastroenterology ◽

10.1016/s0016-5085(20)32767-0 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-835-S-836

Author(s):

Takeo Hara ◽

Hisatsugu Maekawa ◽

Masataka Shimonosono ◽

Rieko Shimonosono ◽

Lauren Dolinsky ◽

...

Keyword(s):

Eosinophilic Esophagitis ◽

Th2 Cytokines ◽

Epithelial Regeneration

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TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts

Scientific Reports ◽

10.1038/s41598-020-74919-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Edward R. Smith ◽

Timothy D. Hewitson

Keyword(s):

Pyruvate Dehydrogenase ◽

Aerobic Glycolysis ◽

Pyruvate Dehydrogenase Complex ◽

Collagen I ◽

Acetyl Coa ◽

Fibroblast Activation ◽

Molecular Events ◽

Molecule Inhibitor ◽

Tgf Β1 ◽

Dehydrogenase Complex

Abstract TGF-β1 reprograms metabolism in renal fibroblasts, inducing a switch from oxidative phosphorylation to aerobic glycolysis. However, molecular events underpinning this are unknown. Here we identify that TGF-β1 downregulates acetyl-CoA biosynthesis via regulation of the pyruvate dehydrogenase complex (PDC). Flow cytometry showed that TGF-β1 reduced the PDC subunit PDH-E1α in fibroblasts derived from injured, but not normal kidneys. An increase in expression of PDH kinase 1 (PDK1), and reduction in the phosphatase PDP1, were commensurate with net phosphorylation and inactivation of PDC. Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation. The effect of TGF-β1 on PDC activity, acetyl-CoA, αSMA and pro-collagen I was also ameliorated by sodium dichloroacetate, a small molecule inhibitor of PDK. A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.

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Calycosin Inhibits Intestinal Fibrosis on CCD-18Co Cells via Modulating Transforming Growth Factor-β/Smad Signaling Pathway

Pharmacology ◽

10.1159/000500186 ◽

2019 ◽

Vol 104 (1-2) ◽

pp. 81-89 ◽

Cited By ~ 3

Author(s):

Jing Liu ◽

Tan Deng ◽

Yaxin Wang ◽

Mengmeng Zhang ◽

Guannan Zhu ◽

...

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Collagen I ◽

Smad Pathway ◽

Smad Signaling ◽

Intestinal Fibrosis ◽

Smad Signaling Pathway ◽

Tgf Β1

Background: Intestinal fibrosis is the major complication of Crohn’s disease (CD). There are no other good treatments for CD except surgery and remains a refractory disease. Calycosin (CA), the active component of astragalus membranaceus, has been reported the potential effect on lung fibrosis and renal fibrosis. In this study, we aim to explore the effect of CA on intestinal fibrosis in vitro and the possible signal pathway. Methods: The antifibrotic effect of CA is investigated in human intestinal fibroblasts (CCD-18Co) cells induced by transforming growth factor-β1 (TGF-β1). MTT method was used to screen the concentration of CA. Real-time polymerase chain reaction and western blot analysis were used to evaluate the expression of α-smooth muscle actin (α-SMA), collagen I, and TGF-β/Smad pathway. Results: The results showed that the concentration of CA was 12.5, 25, 50 μmol/L. CA could inhibit the expression of α-SMA and collagen I. In addition, CA regulated the expression of TGF-β/Smad signaling pathway. Conclusion: This study demonstrated that CA could inhibit the activation of CCD-18Co cells and reduce the expression of extracellular matrix. Our study highlighted that CA-inhibited TGF-β/Smad pathway through inhibiting the expression of p-Smad2, p-Smad3, Smad4, and TGF-β1 and raised the Smad7 expression. Therefore, CA might inhibit intestinal fibrosis by inhibiting the TGF-β/Smad pathway.

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Bacterial cell wall polymers promote intestinal fibrosis by direct stimulation of myofibroblasts

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.277.1.g245 ◽

1999 ◽

Vol 277 (1) ◽

pp. G245-G255 ◽

Cited By ~ 18

Author(s):

Eric A. F. van Tol ◽

Lisa Holt ◽

Feng Ling Li ◽

Feng-Ming Kong ◽

Richard Rippe ◽

...

Keyword(s):

Cell Wall ◽

Bacterial Cell ◽

Intestinal Inflammation ◽

Mesenchymal Cells ◽

Bacterial Cell Wall ◽

Type I ◽

Intestinal Fibrosis ◽

Cell Wall Polymers ◽

Chronic Intestinal Inflammation ◽

Tgf Β1

Normal luminal bacteria and bacterial cell wall polymers are implicated in the pathogenesis of chronic intestinal inflammation. To determine the direct involvement of bacteria and their products on intestinal fibrogenesis, the effects of purified bacterial cell wall polymers on collagen and cytokine synthesis were evaluated in intestinal myofibroblast cultures established from normal fetal and chronically inflamed cecal tissues. In this study, the intestines of Lewis rats were intramurally injected with peptidoglycan-polysaccharide polymers. Collagen and transforming growth factor (TGF)-β1 mRNA levels were measured and correlated with mesenchymal cell accumulation by immunohistochemistry. The direct effects of cell wall polymers on fibrogenic cytokine and collagen α1 (type I) expression were evaluated in intestinal myofibroblast cultures. We found that intramural injections of bacterial cell wall polymers induced chronic granulomatous enterocolitis with markedly increased collagen synthesis and concomitant increased TGF-β1 and interleukin (IL)-6 expression. Intestinal myofibroblast cultures were established, which both phenotypically and functionally resemble the mesenchymal cells that are involved in fibrosis in vivo. Bacterial cell wall polymers directly stimulated collagen α1 (I), TGF-β1, IL-1β, and IL-6 mRNA expression in the intestinal myofibroblasts derived from both normal and inflamed cecum. Neutralization of endogenous TGF-β1 inhibited in vitro collagen gene expression. From our results, we conclude that increased exposure to luminal bacterial products can directly activate intestinal mesenchymal cells, which accumulate in areas of chronic intestinal inflammation, thus stimulating intestinal fibrosis in genetically susceptible hosts.

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