scholarly journals Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGF β1

Aging Cell ◽  
2015 ◽  
Vol 14 (5) ◽  
pp. 774-783 ◽  
Author(s):  
Meredith L. Sosulski ◽  
Rafael Gongora ◽  
Svitlana Danchuk ◽  
Chunmin Dong ◽  
Fayong Luo ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Selective Autophagy ◽  
Tgf Β1

scholarly journals Potential role of senescent macrophages in radiation-induced pulmonary fibrosis

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Lulu Su ◽  
Yinping Dong ◽  
Yueying Wang ◽  
Yuquan Wang ◽  
Bowen Guan ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Pulmonary Fibrosis ◽  
Late Toxicity ◽  
Airway Epithelial ◽  
Tnf Α ◽  
Elevated Expression ◽  
Radiation Induced ◽  
Therapeutic Radiation ◽  
Tgf Β1

AbstractRadiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal+ senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

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 Thymosin β4 protect against LPS induced lung injury and inflammation and subsequent fibrosis in mice

2021 ◽  
Author(s):  
Zhen Tian ◽  
Naijuan Yao ◽  
Fei Wang ◽  
Litao Ruan
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Critical Role ◽  
Protective Role ◽  
Inflammasome Activation ◽  
Thymosin Β4 ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background: Inflammation plays a critical role in the progression of pulmonary fibrosis. Thymosin β4 (Tβ4) has antioxidant, anti-inflammatory and antifibrotic effects. Although the potent protective role of Tβ4 in bleomycin-induced pulmonary fibrosis has been validated, the mechanism is not clear, and its impact on lipopolysaccharide (LPS)-induced lung injury/fibrosis has not been reported. Method: Expression of Tβ4 in fibrotic lung tissues was assessed by real-time quantitative reverse transcriptase PCR (RQ-PCR), immunohistochemistry (IHC) and Western Blotting. The effects of intraperitoneal adeno-associated virus-Tβ4 (AAV-Tβ4) on LPS-induced lung injury and fibrosis were observed through the evaluation of collagen deposition and α-smooth muscle actin (SMA) expression. In vitro tests with HPAEpiC and HLF-1 cells were performed to confirm the effects of Tβ4.Results: In this study, we evaluated the role of Tβ4 in pulmonary fibrosis and explored the possible underlying mechanisms. We found that Tβ4 was markedly upregulated in human or mouse fibrotic lung tissues. AAV-Tβ4 markedly alleviated LPS-induced oxidative damage, lung injury, inflammation, and fibrosis in mice. Our in vitro experiments also showed that LPS inhibited mitophagy and promoted inflammation via oxidative stress in HPAEpiC, and usage of Tβ4 significantly attenuated LPS-induced mitophagy inhibition, inflammasome activation and transforming growth factor-β (TGF)-β1 induced epithelial-mesenchymal transition (EMT) in HPAEpiC. Moreover, we found that Tβ4 suppressed the proliferation and attenuated the TGF-β1-induced activation of HLF-1 cells. Conclusions: In conclusion, Tβ4 alleviates LPS-induced lung injury, inflammation, and subsequent fibrosis in mice, suggesting a protective role of Tβ4 in disease pathogenesis of pulmonary fibrosis (PF). Tβ4 involves in attenuating oxidative injury, promoting mitophagy, and then alleviating inflammation and fibrosis. Modulating of Tβ4 might be a novel strategy for treating PF.

scholarly journals Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

2020 ◽  
Author(s):  
Guichuan Huang ◽  
Jing Zhang ◽  
Gang Qing ◽  
Daishun Liu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Tgf Β1

Abstract Background：Pulmonary fibrosis (PF) is a progressive and lethal disease with poor prognosis. S100A2 plays an important role in the progression of cancer. However, the role of S100A2 in PF has not been reported yet. In this study, we explored the potential role of S100A2 in PF and its potential molecular mechanisms. Methods: First, we analyzed S100A2 expression of patients with PF by retrieving RNA-sequencing datasets from Gene Expression Omnibus (GEO) database. Next, we detected the expression of S100A2 in patients with PF using quantitative real time PCR (qRT-PCR). Then, S100A2 expression was determined with or without the treatment of transforming growth factor-β1 (TGF-β1) in A549 cells. Epithelial-mesenchymal transition (EMT) biomarkers, including E-cadherin，vimentin, and α smooth muscle actin (α-SMA), were identified using qRT-PCR and western blot. Finally, the relevant signalling pathway indicators were detected by western blot. Results: Increased expression of S100A2 was first observed in lung tissues of PF patients. Meanwhile, we found that downregulation of S100A2 inhibited the TGF-β1-induced EMT in A549 cells. Mechanically, TGF-β1 up-regulated β-catenin and phosphorylation of GSK-3β, which was blocked by silencing S100A2 in vitro. Conclusion: These findings demonstrate that downregulation of S100A2 alleviate pulmonary fibrosis via inhibiting EMT. S100A2 is a promising potential target for further understanding the mechanism and developing strategy for the treatment of PF and other EMT-associated disease.

PPP2R3A Affects the Function and Mechanism of Heterogeneous Fibroblasts in Pulmonary Fibrosis

2021 ◽  
Author(s):  
Xiaoni Shi ◽  
Shaoqi Yang ◽  
Wei Luo ◽  
Sha Wang ◽  
Jie Huang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Physiological Saline ◽  
Cell Counting ◽  
Lesion Area ◽  
And Migration ◽  
Remodeling Of Extracellular Matrix ◽  
Interfering Rna ◽  
Tgf Β1 ◽  
Proliferation And Migration

Abstract Background: Fibroblasts have important roles in the synthesis and remodeling of extracellular matrix (ECM) proteins during pulmonary fibrosis. However, the spatiotemporal distribution of heterogeneous fibroblasts during disease progression remains unknown. Methods: Physiological saline and silica were used to generate a chronic pulmonary fibrosis model in mice, and single-cell sequencing, spatial transcriptome sequencing, real-time fluorescent quantitative PCR, immunohistochemistry and immunofluorescence were performed to identify fibroblast subtypes. Small interfering RNA was used to specifically knockdown the target protein, and western blotting, bromodeoxyuridine (BrdU), Cell Counting Kit-8 (CCK-8) and wound healing assays were used to detect the role of GREM1/PPP2R3A in a newly identified fibroblast subtype. Results: Fibroblasts of the new subtype were mainly located in the lesion area and coexpressed inflammation- and proliferation-related genes; they were termed inflammatory-proliferation fibroblasts. Grem1 was the most highly expressed gene in this subtype, as confirmed in HPF-a cells after TGF-β1 treatment. We characterized the downstream mechanism of GREM1/PPP2R3A: these factors mediated the increases in cell viability, proliferation and migration induced by TGF-β1 in fibroblasts. Conclusion: This new subtype of inflammatory, proliferative fibroblasts plays a pivotal role during pulmonary fibrosis, and PPP2R3A, as a downstream regulatory target of GREM1, is involved in pulmonary fibrosis, providing new insights for the prevention and treatment of silicosis.

TRIM33 prevents pulmonary fibrosis by impairing TGF-β1 signalling

2020 ◽  
Vol 55 (6) ◽  
pp. 1901346 ◽  
Author(s):  
Pierre-Marie Boutanquoi ◽  
Olivier Burgy ◽  
Guillaume Beltramo ◽  
Pierre-Simon Bellaye ◽  
Lucile Dondaine ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Tissue ◽  
Transforming Growth Factor ◽  
Small Heat Shock Protein ◽  
Negative Regulator ◽  
Lung Fibroblasts ◽  
Tissue Slices ◽  
Tgf Β1

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-β1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF.MethodsTRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from Trim33-floxed mice and cultured with TGF-β1 or bleomycin (BLM). Trim33 expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific Trim33 knockout mice and in Trim33-floxed mice that received AdCre and BLM intratracheally.ResultsTRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. Trim33 inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction.ConclusionOur results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.

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 Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenzhen Ma ◽  
Chunyan Ma ◽  
Qingfeng Zhang ◽  
Yang Bai ◽  
Kun Mu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

AbstractAlveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

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.

Sign in / Sign up

Export Citation Format

Share Document