scholarly journals Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Qun Lv ◽  
Jianjun Wang ◽  
Changqing Xu ◽  
Xuqing Huang ◽  
Zhaoyang Ruan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Gsk 3Β ◽  
Tgf Β1

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 Protective Effect of Remdesivir Against Pulmonary Fibrosis in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohe Li ◽  
Rui Liu ◽  
Yunyao Cui ◽  
Jingjing Liang ◽  
Zhun Bi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Antiviral Drug ◽  
Alveolar Epithelial Cells ◽  
Lung Damage ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

Pulmonary fibrosis is a known sequela of severe or persistent lung damage. Existing clinical, imaging and autopsy studies have shown that the lungs exhibit a pathological pulmonary fibrosis phenotype after infection with coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary fibrosis may be one of the most serious sequelae associated with coronavirus disease 2019 (COVID-19). In this study, we aimed to examine the preventative effects of the antiviral drug remdesivir on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of remdesivir on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of remdesivir in lung fibroblasts and alveolar epithelial cells in vitro. The preventive remdesivir treatment was started on the day of bleomycin installation, and the results showed that remdesivir significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro experiments showed that remdesivir dose-dependently suppressed TGF-β1-induced lung fibroblast activation and improved TGF-β1-induced alveolar epithelial to mesenchymal transition. Our results indicate that remdesivir can preventatively alleviate the severity of pulmonary fibrosis and provide some reference for the prevention of pulmonary fibrosis in patients with COVID-19.

scholarly journals Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Zhen-feng Hou ◽  
Hao-yue Zhu ◽  
Xiao-xuan Chen ◽  
Wan-yang Li ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Gene Expression Omnibus ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Collagen Remodeling ◽  
Gsk 3Β ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

scholarly journals Schisantherin A Inhibits Pulmonary Fibrosis via Regulating ERK Signaling Pathway

2020 ◽  
Vol 15 (8) ◽  
pp. 1934578X2094835
Author(s):  
Wenyue Zhuang ◽  
Na Zhao ◽  
Di Li ◽  
Xiaoming Su ◽  
Yueyang Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Western Blot ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Erk Signaling ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
Schisantherin A

There is no effective method for treating pulmonary fibrosis (PF) until now. This study investigated the anti-fibrotic effect of schisantherin A (SCA) extracted from Schisandra chinensis and its potential molecular mechanism in PF. A bleomycin-induced PF mouse model in vivo and transforming growth factor (TGF)-β1-induced A549 epithelial-mesenchymal transition (EMT) cell model in vitro were used for assessing the anti-fibrotic effect of SCA. Histopathological examination was conducted after hematoxylin and eosin and Masson staining. The level of TGF-β1 was tested by ELISA. The expression levels of α-smooth muscle actin, E-cadherin, and inflammatory cytokines (COX2, IL-1β, IL-6, and TNF-α) were determined by quantitative reverse transcription polymerase chain reaction and Western blot. The expression of extracellular signal-regulated kinase (ERK) was tested in lung tissues and cells by Western blot. The in vivo experiments revealed that SCA treatment markedly improved body weight and pulmonary index and reformed the destruction of the lung tissue structure. We observed that SCA inhibited the process of TGF-β1-induced EMT in the in vitro experiments. Inflammatory cytokines were reduced greatly in lung tissues and cells by SCA. Our study also indicated that SCA decreased phosphorylated ERK. It was concluded that SCA can attenuate PF by regulating the ERK signaling pathway, which suggests that SCA may be used as a potential therapeutic drug for PF.

scholarly journals Total extract of Xin Jia Xuan Bai Cheng Qi decoction inhibits pulmonary fibrosis via the TGF-β/Smad signaling pathways in vivo and in vitro

2019 ◽  
Vol Volume 13 ◽  
pp. 2873-2886 ◽  
Author(s):  
Hui Qin ◽  
Hao-Tian Wen ◽  
Kai-Juan Gu ◽  
Xu-Dong Hu ◽  
Tao Yang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Total Extract ◽  
Smad Signaling

scholarly journals Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial–mesenchymal transition inhibition in vitro and in vivo

2021 ◽  
Author(s):  
Lin Chen ◽  
Azeem Alam ◽  
Aurelie Pac-Soo ◽  
Qian Chen ◽  
You Shang ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Body Weight ◽  
Survival Rate ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
E Cadherin

AbstractEpithelial–mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-β1 (TGF-β1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1–3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-β1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-β type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-β1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-β1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement.

scholarly journals Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yufeng Yao ◽  
Yue Yuan ◽  
Zenghui Lu ◽  
Yunxia Ma ◽  
Yuanyuan Xie ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Therapeutic Effects ◽  
Collagen Deposition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.

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