scholarly journals Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

2021 ◽  
Author(s):  
Loka Raghu Kumar Penke ◽  
Jennifer Speth ◽  
Scott Wettlaufer ◽  
Christina Draijer ◽  
Marc Peters-Golden
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Proteasome Inhibition ◽  
Fibroblast Activation ◽  
Dual Specificity ◽  
Therapeutic Administration ◽  
Proteasomal Inhibitor ◽  
Characteristic Resistance

The FDA-approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential anti-fibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. Herein, we identify that therapeutic administration of BTZ in a mouse model of pulmonary fibrosis diminished the severity of fibrosis without reducing proteasome activity in the lung. Under conditions designed to mimic this lack of proteasome inhibition in vitro, it reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted de-differentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing expression of dual-specificity phosphatase 1 or DUSP1, and knockdown of DUSP1 abolished its anti-fibrotic actions in fibroblasts. Our findings identify a novel proteasome-independent mechanism of anti-fibrotic actions for BTZ and support its therapeutic repurposing for pulmonary fibrosis.

scholarly journals Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Caijuan Huan ◽  
Ting Yang ◽  
Jiurong Liang ◽  
Ting Xie ◽  
Luis Cheng ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Fibroblast Activation

scholarly journals Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/β-Catenin Pathway in PQ-Induced Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fei Gao ◽  
Yun Zhang ◽  
Zhizhou Yang ◽  
Mengmeng Wang ◽  
Zhiyi Zhou ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Alveolar Type ◽  
Mesenchymal Transition

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

scholarly journals Dual Effects of Hypoxia-Inducible Factors-1 Alpha in Bleomycin-Induced Pulmonary Fibrosis Treated by Human Umbilical Cord Mesenchymal Stem Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hongpeng Zhang ◽  
Hao Wang ◽  
Yong Xia ◽  
Nianmin Qi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Pulmonary Fibrosis ◽  
Umbilical Cord ◽  
Smooth Muscle Actin ◽  
A549 Cells ◽  
Human Umbilical Cord ◽  
Therapeutic Administration

Pulmonary fibrosis (PF) is a kind of lung disease characterized by scar formation and inflammation damage. Mesenchymal stem cells (MSCs) are considered a promising therapy because of multidirectional differentiation and immune regulation. Our research was designed for identifying the preventative defensive ability and therapeutic effect of human umbilical cord mesenchymal stem cells (HUCMSCs). HUCMSCs were administered before or after bleomycin injection in different groups of C57BL/6 mice. We calculated the survival time of mice, the lung coefficients, contents of hydroxyproline, and pathological scores. The expression levels of HIF-1α (hypoxia-inducible factor-1α), α-SMA (α-smooth muscle actin), γH2AFX (γH2A histone family, member X), ZO-1 (zonula occludens-1), ROS (reactive oxygen species) content, and proliferation ability of A549 cells were detected after treatment with bleomycin and HUCMSCs conditioned medium (HUCMSCs-CM), respectively, or together in vitro. In addition, we examined the secretome of HUCMSCs in regular and inflammatory stimulation conditions. Our results demonstrated that prophylactic HUCMSC administration before bleomycin-induced modeling process could significantly meliorate damage to pulmonary fibrosis. After the deletion of HIF-1α, damage markers in A549 cells were significantly reduced in therapeutic administration condition. However, it was the opposite in prophylactic administration condition. The results confirmed that HUCMSCs had available preventive effect on bleomycin-induced pulmonary fibrosis in vivo and in vitro. However, it may have a negative effect in therapeutic administration condition because of the dual effect of HIF-1α.

scholarly journals Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Caijuan Huan ◽  
Wangting Xu ◽  
Yaru Liu ◽  
Kexin Ruan ◽  
Yueli Shi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Fetal Lung ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Matricellular Proteins ◽  
Matrix Deposition

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-β (TGF-β) superfamily involves bone morphogenetic proteins (BMPs) and TGF-β, and the balance between the activation of TGF-β-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-β-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-β/BMP signaling, in which Gremlin2 may activate TGF-β signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.

scholarly journals Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Wen-yu-jin Against Pulmonary Fibrosis in Mouse Model

2021 ◽  
Author(s):  
lu wang ◽  
Wenxiang Zhu ◽  
Rui Sun ◽  
Jing Liu ◽  
Qihong Ma ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Network Pharmacology ◽  
In Vitro Experiments

Abstract Background Pulmonary fibrosis (PF) is a devastating lung disease. The two drugs approved by the FDA, pirfenidone and nintedanib, can only delay the progression of the disease but cannot cure the disease. These drugs also present adverse effects. Wen-yu-jin (WYJ) obtained from steamed roots of Curcuma wenyujin showed a variety of pharmacological activities. In this study we investigated whether WYJ present anti-lung fibrosis effects. Methods Ultra-high pressure liquid chromatography combined with linear ion trap-orbital tandem mass spectrometry (UHPLC-LTQ-orbital trap) was used to identify chemical composition of WYJ. PF-related and WYJ-related targets were obtained from public databases. Network pharmacological was performed to acquire potential targets and major signaling pathways. The binding activity of composition with core targets was predicted by molecular docking. Based on the predicted results, the anti-lung fibrosis effect of WYJ was verified in vivo and in vitro experiments. Results 23 major compositions of WYJ were identified based on UHPLC-LTQ-Orbitrap. According to the results of network pharmacology, MAPK signaling pathway might play an important role in WYJ against lung fibrosis and STAT3 also could be the potential therapeutic targets. Molecular docking results indicated that most of the compositions have good binding activities with core targets. In vivo and in vitro experiments showed that WYJ alleviated process of fibrosis by inhibiting MAPK signaling pathway and the levels of phosphorylated STAT3 (p-STAT3). Conclusion According to the results of network pharmacology and molecular docking, in vivo and in vitro experiments further verified potential targets and molecular mechanism of WYJ against lung fibrosis. Our study provided a novel approach to explain the pharmacological basis of other herbs.

scholarly journals Human-Based Advanced in vitro Approaches to Investigate Lung Fibrosis and Pulmonary Effects of COVID-19

2021 ◽  
Vol 8 ◽  
Author(s):  
Mirjam Kiener ◽  
Nuria Roldan ◽  
Carlos Machahua ◽  
Arunima Sengupta ◽  
Thomas Geiser ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Tissue Regeneration ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Diffuse Alveolar Damage ◽  
Treatment Strategies ◽  
Current Evidence ◽  
Micro Particles

The coronavirus disease 2019 (COVID-19) pandemic has caused considerable socio-economic burden, which fueled the development of treatment strategies and vaccines at an unprecedented speed. However, our knowledge on disease recovery is sparse and concerns about long-term pulmonary impairments are increasing. Causing a broad spectrum of symptoms, COVID-19 can manifest as acute respiratory distress syndrome (ARDS) in the most severely affected patients. Notably, pulmonary infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the causing agent of COVID-19, induces diffuse alveolar damage (DAD) followed by fibrotic remodeling and persistent reduced oxygenation in some patients. It is currently not known whether tissue scaring fully resolves or progresses to interstitial pulmonary fibrosis. The most aggressive form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease that progressively destroys alveolar architecture by uncontrolled fibroblast proliferation and the deposition of collagen and extracellular matrix (ECM) proteins. It is assumed that micro-injuries to the alveolar epithelium may be induced by inhalation of micro-particles, pathophysiological mechanical stress or viral infections, which can result in abnormal wound healing response. However, the exact underlying causes and molecular mechanisms of lung fibrosis are poorly understood due to the limited availability of clinically relevant models. Recently, the emergence of SARS-CoV-2 with the urgent need to investigate its pathogenesis and address drug options, has led to the broad application of in vivo and in vitro models to study lung diseases. In particular, advanced in vitro models including precision-cut lung slices (PCLS), lung organoids, 3D in vitro tissues and lung-on-chip (LOC) models have been successfully employed for drug screens. In order to gain a deeper understanding of SARS-CoV-2 infection and ultimately alveolar tissue regeneration, it will be crucial to optimize the available models for SARS-CoV-2 infection in multicellular systems that recapitulate tissue regeneration and fibrotic remodeling. Current evidence for SARS-CoV-2 mediated pulmonary fibrosis and a selection of classical and novel lung models will be discussed in this review.

scholarly journals microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhou ◽  
Yang Lin ◽  
Xiuhua Kang ◽  
Zhicheng Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Extracellular Vesicles ◽  
Luciferase Assay ◽  
Therapeutic Effects ◽  
Loss Of Function ◽  
Fibroblast Activation ◽  
Promising Therapeutic Approach

Abstract Background Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model. Methods In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1). Results BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1. Conclusion In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

Sign in / Sign up

Export Citation Format

Share Document