Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-β1/BMP-4 signaling

2019 ◽  
Vol 400 (12) ◽  
pp. 1617-1627
Author(s):  
Meizi Chen ◽  
Bing Wan ◽  
Suhua Zhu ◽  
Fang Zhang ◽  
Jiajia Jin ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Morphogenetic Protein ◽  
Tgf Β1

Abstract Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme that catalyzes the synthesis of geranylgeranyl pyrophosphate (GGPP). GGPPS is implicated in many disorders, but its role in idiopathic pulmonary fibrosis (IPF) remains unclear. This study aimed to investigate the role of GGPPS in IPF. We established bleomycin-induced lung injury in a lung-specific GGPPS-deficient mouse (GGPPS−/−) and detected GGPPS expression in lung tissues by Western blot and immunohistochemistry analysis. We found that GGPPS expression increased during lung injury and fibrosis in mice induced by bleomycin, and GGPPS deficiency augmented lung fibrosis. GGPPS deficiency activated lung fibroblast by facilitating transforming growth factor β1 while antagonizing bone morphogenetic protein 4 signaling. Notably, the supplementation of exogenous GGPP mitigated lung fibrosis in GGPPS−/− mice induced by bleomycin. In conclusion, our findings suggest that GGPPS provides protection against pulmonary fibrosis and that the restoration of protein geranylgeranylation may benefit statin-induced lung injury.

scholarly journals Lung Fibrosis-associated Surfactant Protein A1 and C Variants Induce Latent Transforming Growth Factor β1 Secretion in Lung Epithelial Cells

2013 ◽  
Vol 288 (38) ◽  
pp. 27159-27171 ◽  
Author(s):  
Meenakshi Maitra ◽  
Moushumi Dey ◽  
Wen-Cheng Yuan ◽  
Peter W. Nathanielsz ◽  
Christine Kim Garcia
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Surfactant Protein ◽  
Transforming Growth Factor Β1 ◽  
Lung Epithelial Cells ◽  
Missense Mutations ◽  
Lung Epithelial ◽  
Tgf Β1

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

scholarly journals Inhibition of lncRNA PFRL prevents pulmonary fibrosis by disrupting the miR-26a/smad2 loop

2018 ◽  
Vol 315 (4) ◽  
pp. L563-L575 ◽  
Author(s):  
Hua Jiang ◽  
Yingzhun Chen ◽  
Tong Yu ◽  
Xiaoguang Zhao ◽  
Huitong Shan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Feedback Loop ◽  
Transforming Growth Factor ◽  
Molecular Study ◽  
Pulmonary Fibroblasts ◽  
Proliferation And Differentiation ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with increasing mortality and poor prognosis. The current understanding of the role of long noncoding RNAs (lncRNAs) in IPF remains limited. In the present study, we identified a lncRNA NONMMUT022554, designated pulmonary fibrosis-regulatory lncRNA (PFRL), with unknown functions and found that its levels were increased in fibrotic lung tissues of mice and pulmonary fibroblasts exposed to transforming growth factor (TGF)-β1. Furthermore, we found that enforced expression of PFRL induced fibroblast activation and collagen deposition, which could be mitigated by the overexpression of microRNA (miR)-26a. By contrast, the inhibition of PFRL could markedly alleviate the TGF-β1-induced upregulation of fibrotic markers and attenuate fibroblast proliferation and differentiation by regulating miR-26a. Meanwhile, our study confirmed that PFRL inhibited the expression and activity of miR-26a, which has been identified as an antifibrotic miRNA in our previous study. Interestingly, our molecular study further confirmed that Smad2 transcriptionally inhibits the expression of miR-26a and that the miR-26a/Smad2 feedback loop mediates the profibrotic effects of PFRL in lung fibrosis. More importantly, knockdown of PFRL ablated bleomycin-induced pulmonary fibrosis in vivo. Taken together, our findings indicate that lncRNA PFRL contributes to the progression of lung fibrosis by modulating the reciprocal repression between miR-26a and Smad2 and that this lncRNA may be a therapeutic target for IPF.

The role of macrophage-derived TGF-β1 on SiO2-induced pulmonary fibrosis: A review

2021 ◽  
pp. 074823372198989
Author(s):  
Zhao-qiang Zhang ◽  
Hai-tao Tian ◽  
Hu Liu ◽  
Ruining Xie
Keyword(s):  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Silica Dust ◽  
Molecular Events ◽  
Fibrotic Lung Disease ◽  
Different Sources ◽  
Tgf Β1

Silicosis is an occupational fibrotic lung disease caused by inhaling large amounts of crystalline silica dust. Transforming growth factor-β1 (TGF-β1), which is secreted from macrophages, has an important role in the development of this disease. Macrophages can recognize and capture silicon dust, undergo M2 polarization, synthesize TGF-β1 precursors, and secrete them out of the cell where they are activated. Activated TGF-β1 induces cells from different sources, transforming them into myofibroblasts through autocrine and paracrine mechanisms, ultimately causing silicosis. These processes involve complex molecular events, which are not yet fully understood. This systematic summary may further elucidate the location and development of pulmonary fibrosis in the formation of silicosis. In this review, we discussed the proposed cellular and molecular mechanisms of production, secretion, activation of TGF-β1, as well as the mechanisms through which TGF-β1 induces cells from three different sources into myofibroblasts during the pathogenesis of silicosis. This study furthers the medical understanding of the pathogenesis and theoretical basis for diagnosing silicosis, thereby promoting silicosis prevention and treatment.

scholarly journals Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Demin Cheng ◽  
Qi Xu ◽  
Yue Wang ◽  
Guanru Li ◽  
Wenqing Sun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. Methods The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-β1)-induced differentiated lung fibroblasts were used for in vitro models. Results At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2–10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-β1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. Conclusions In this study, we identified that metformin might be a potential drug for silicosis treatment.

scholarly journals LncRNA SNHG16 promotes pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Panpan Liu ◽  
Lei Zhao ◽  
Yuxia Gu ◽  
Meilan Zhang ◽  
Hongchang Gao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interstitial Lung Diseases ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
And Migration

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung diseases with a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to be involved in IPF in several studies. However, the role of lncRNA SNHG16 in IPF is largely unknown. Methods Firstly, experimental pulmonary fibrosis model was established by using bleomycin (BML). Histology and Western blotting assays were used to determine the different stages of fibrosis and expression of several fibrosis biomarkers. The expression of SNHG16 was detected by quantitative real-time polymerase chain reaction (qRT‐PCR). EdU staining and wound-healing assay were utilized to analyze proliferation and migration of lung fibroblast cells. Molecular mechanism of SNHG16 was explored by bioinformatics, dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and qRT-PCR. Results The expression of SNHG16 was significantly up-regulated in bleomycin-(BLM) induced lung fibrosis and transforming growth factor-β (TGF-β)-induced fibroblast. Knockdown of SNHG16 could attenuate fibrogenesis. Mechanistically, SNHG16 was able to bind and regulate the expression of miR-455-3p. Moreover, SNHG16 also regulated the expression of Notch2 by targeting miR-455-3p. Finally, SNHG16 could promote fibrogenesis by regulating the expression of Notch2. Conclusion Taken together, our study demonstrated that SNHG16 promoted pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway. These findings might provide a novel insight into pathologic process of lung fibrosis and may provide prevention strategies in the future.

scholarly journals microRNA-145-5p attenuates acute lung injury via targeting ETS2

2021 ◽  
Author(s):  
Liang Qiao ◽  
Rongxia Li ◽  
Shangang Hu ◽  
Yu Liu ◽  
Hongqiang Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Growth Factor ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Recombinant Adenovirus ◽  
Transforming Growth Factor Β1 ◽  
Inflammatory Factors ◽  
Smad Pathway ◽  
Tgf Β1

Abstract Objective Previously, the protective effect of microRNA (miR)-145-5p has been discovered in acute lung injury (ALI). Thus, this study attempts to further discuss the mechanism of miR-145-5p in ALI through the downstream E26 transformation-specific proto-oncogene 2 (ETS2)/transforming growth factor β1 (TGF-β1)/Smad pathway. Methods A lipopolysaccharide (LPS)-induced rat ALI model was established. Recombinant adenovirus miR-145-5p and/or ETS2 overexpression plasmid was administrated into rats. Afterwards, pathological damage in the lung tissue, wet/dry (W/D) ratio, apoptosis and contents of serum inflammatory factors were observed. miR-145-5p, ETS2, TGF-β1, Smad2/3, phosphorylated Smad2/3 levels were measured in rats. Results miR-145-5p was down-regulated, ETS2 was up-regulated and TGF-β1/Smad pathway was activated in LPS-suffered rats. Overexpression of miR-145-5p inactivated the TGF-β1/Smad pathway and attenuated ALI, as reflected by relived pathological damage, and decreased W/D ratio, apoptosis and inflammatory response. Oppositely, loss of miR-145-5p or enhancement of ETS2 worsened ALI and activated the TGF-β1/Smad pathway. Moreover, elevation of ETS2 decreased miR-145-5p-mediated protection against ALI. Conclusion Evidently, miR-145-5p negatively regulates ETS2 expression and inactivates TGF-β1/Smad pathway to ameliorate ALI in rats.

scholarly journals Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

2020 ◽  
Vol 48 (16) ◽  
pp. 8943-8958 ◽  
Author(s):  
Antonio Pezone ◽  
Maria Letizia Taddei ◽  
Alfonso Tramontano ◽  
Jacopo Dolcini ◽  
Francesca Ludovica Boffo ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Dna Oxidation ◽  
Mesenchymal Transition ◽  
Kinase C ◽  
Histone Lysine ◽  
Lysine Specific Demethylase ◽  
Tgf Β1

Abstract The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT.

scholarly journals Expression and Clinical Significance of Mucin Gene in Chronic Rhinosinusitis

2020 ◽  
Vol 20 (11) ◽  
Author(s):  
Jiaxin Tong ◽  
Qingjia Gu
Keyword(s):  
Chronic Rhinosinusitis ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β1 ◽  
Inflammatory Factors ◽  
Human Neutrophil Elastase ◽  
Mucin Expression ◽  
Nasal Disease ◽  
Tgf Β1

Abstract Purpose of Review This review highlights the expression and regulation of mucin in CRS and discusses its clinical implications. Recent Findings Chronic rhinosinusitis (CRS) is common chronic nasal disease; one of its main manifestations and important features is mucus overproduction. Mucin is the major component of mucus and plays a critical role in the pathophysiological changes in CRS. The phenotype of CRS affects the expression of various mucins, especially in nasal polyps (NP). Corticosteroids(CS), human neutrophil elastase (HNE), and transforming growth factor-β1 (TGF-β1) are closely related to the tissue remodeling of CRS and regulate mucin expression, mainly MUC1, MUC4, MUC5AC, and MUC5B. “It is expected that CS, HNE and TGF - β could be used to regulate the expression of mucin in CRS.” However, at present, the research on mucin is mainly focused on mucin 5AC and mucin 5B, which is bad for finding new therapeutic targets. Summary Investigating the expression and location of mucin in nasal mucosa and understanding the role of various inflammatory factors in mucin expression are helpful to figure out regulatory mechanisms of airway mucin hypersecretion. It is of great significance for the treatment of CRS.

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