Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling

2018 ◽  
Vol 96 (6) ◽  
pp. 742-751 ◽  
Author(s):  
Xingcai Zhang ◽  
Yuli Cai ◽  
Wei Zhang ◽  
Xianhai Chen
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Ectopic Expression ◽  
High Morbidity ◽  
Human Embryonic Lung ◽  
Pulmonary Tissue ◽  
Collagen Iii

Idiopathic pulmonary fibrosis is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I, and Collagen III. Similar results were observed in transforming growth factor (TGF)-β-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-β administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1, and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.

Inhibition of miR-182-5p attenuates pulmonary fibrosis via TGF-β/Smad pathway

2019 ◽  
Vol 39 (5) ◽  
pp. 683-695 ◽  
Author(s):  
Y Chen ◽  
Q Zhang ◽  
Y Zhou ◽  
Z Yang ◽  
M Tan
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lung Fibroblasts ◽  
In Vitro Assays ◽  
Luciferase Reporter ◽  
High Morbidity ◽  
Human Embryonic Lung ◽  
Promising Therapeutic Approach ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with high morbidity and mortality. miR-182-5p is overexpressed in several fibrosis-related diseases but its effect in pulmonary fibrosis has not been reported yet. To investigate the function of miR-182-5p in pulmonary fibrosis, we established bleomycin (BLM)-induced fibrotic mice model and transforming growth factor-β1 (TGF-β1)-treated human embryonic lung fibroblasts model. In this study, miR-182-5p was highly expressed in pulmonary tissues of BLM-induced fibrotic mice. The content of hydroxyproline and TGF-β1 was decreased by downregulating the expression of miR-182-5p, indicating that fibrosis was alleviated in mice treated with Lentivirus-anti-miR-182-5p.Quantification of fibrosis-related proteins demonstrated that downregulation of miR-182-5p inhibited the expression of profibrotic proteins (fibronectin, α-smooth muscle actin, p-Smad2/p-Smad3) as well as enhanced the level of Smad7. In vitro assays validated that miR-182-5p was induced by TGF-β1 with the function of promoting fibrosis. In dual-luciferase reporter assay, Smad7 was demonstrated to be negatively regulated by miR-182-5p. Moreover, the effect of knocking down miR-182-5p on inhibiting fibrosis was achieved by upregulating the expression of Smad7. Therefore, miR-182-5p can be regarded as a biomarker of IPF and its inhibition may be a promising therapeutic approach in treating IPF.

scholarly journals Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Shu-xian Li ◽  
Chao Li ◽  
Xin-ru Pang ◽  
Juan Zhang ◽  
Gong-chang Yu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mammalian Target Of Rapamycin ◽  
Specific Treatment ◽  
Transforming Growth Factor Β1 ◽  
Silica Particles ◽  
Protein Levels

Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.

scholarly journals Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice

2017 ◽  
Vol 312 (5) ◽  
pp. L741-L747 ◽  
Author(s):  
Hongge Ma ◽  
Shupei Qiao ◽  
Zeli Wang ◽  
Shuai Geng ◽  
Yufang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Genetically Engineered ◽  
Hek293 Cells ◽  
High Morbidity ◽  
Type I

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.

scholarly journals Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Xia Yang ◽  
Jia-Huan Sun ◽  
Ting-Ting Yao ◽  
Yuan Li ◽  
Geng-Rui Xu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Animal Studies ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Myocardial Damage ◽  
High Morbidity ◽  
Cytoplasmic Localization ◽  
Tgf Β1

Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett (G. acuta) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against myocardial damage. However, the effects and mechanisms of BEL on myocardial fibrosis have not been reported. In vivo, BEL dampened isoprenaline (ISO)-induced cardiac structure disturbance and collagen deposition. In vitro, BEL inhibited transforming growth factor (TGF)-β1-induced cardiac fibroblast (CF) proliferation. In vivo and in vitro, BEL decreased the expression of α-smooth muscle actin (α-SMA), collagen Ⅰ and Ⅲ, and inhibited TGF-β1/Smads signaling. Additionally, BEL impeded p38 activation and NR4A1 (an endogenous inhibitor for pro-fibrogenic activities of TGF-β1) phosphorylation and inactivation in vitro. In CFs, inhibition of p38 by SB203580 inhibited the phosphorylation of NR4A1 and did not limit Smad3 phosphorylation, and blocking TGF-β signaling by LY2157299 and SB203580 could decrease the expression of α-SMA, collagen I and III. Overall, both cell and animal studies provide a potential role for BEL against myocardial fibrosis by inhibiting the proliferation and phenotypic transformation of CFs. These inhibitory effects might be related to regulating TGF-β1/Smads pathway and p38 signaling and preventing NR4A1 cytoplasmic localization.

scholarly journals Tirbanibulin Attenuates Pulmonary Fibrosis by Modulating Src/STAT3 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Wang ◽  
Rui Ren ◽  
Zehui Xu ◽  
Haidi Huang ◽  
Wanglin Jiang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
Collagen I ◽  
L929 Cells ◽  
Signal Transducers ◽  
Stat3 Signaling ◽  
Collagen Iii ◽  
The Impact

Tirbanibulin (KX-01) is the first clinical Src inhibitor of the novel peptidomimetic class that targets the peptide substrate site of Src providing more specificity toward the Src kinase. This study assessed the impact of KX-01 on cobalt chloride (CoCl2)-treated L929 cells and bleomycin (BLM)-induced pulmonary fibrosis in rats to evaluate the efficacy of this compound in vitro and in vivo, respectively. In CoCl2-treated L929 cells, KX-01 significantly reduced the expression of smooth muscle actin (α-SMA), collagen I, collagen III, hypoxia inducing factor (HIF-1α), signal transducers and transcriptional activators (p-STAT3), and p-Src. In BLM-induced pulmonary fibrosis rats, KX-01 reduced pathological scores, collagen deposition, α-SMA, collagen I, collagen III, p-Src, HIF-1α, and p-STAT3. Overall, these findings revealed that KX-01 can alleviate experimental pulmonary fibrosis via suppressing the p-SRC/p-STAT3 signaling pathways.

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 mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nozomi Igarashi ◽  
Megumi Honjo ◽  
Makoto Aihara
Keyword(s):  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mtor Inhibitors ◽  
In Vivo Model ◽  
Type I ◽  
Fibrotic Response ◽  
Alpha Smooth Muscle Actin

AbstractWe examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.

scholarly journals Di-Tyrosine Crosslinking and NOX4 Expression as Oxidative Pathological Markers in the Lungs of Patients with Idiopathic Pulmonary Fibrosis

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1833
Author(s):  
Sanja Blaskovic ◽  
Yves Donati ◽  
Isabelle Ruchonnet-Metrailler ◽  
Tamara Seredenina ◽  
Karl-Heinz Krause ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Post Translational Modification ◽  
Pulmonary Tissue ◽  
Nadph Oxidase 4

Idiopathic pulmonary fibrosis (IPF) is a noninflammatory progressive lung disease. Oxidative damage is a hallmark of IPF, but the sources and consequences of oxidant generation in the lungs are unclear. In this study, we addressed the link between the H2O2-generating enzyme NADPH oxidase 4 (NOX4) and di-tyrosine (DT), an oxidative post-translational modification in IPF lungs. We performed immunohistochemical staining for DT and NOX4 in pulmonary tissue from patients with IPF and controls using validated antibodies. In the healthy lung, DT showed little or no staining and NOX4 was mostly present in normal vascular endothelium. On the other hand, both markers were detected in several cell types in the IPF patients, including vascular smooth muscle cells and epithelium (bronchial cells and epithelial cells type II). The link between NOX4 and DT was addressed in human fibroblasts deficient for NOX4 activity (mutation in the CYBA gene). Induction of NOX4 by Transforming growth factor beta 1 (TGFβ1) in fibroblasts led to moderate DT staining after the addition of a heme-containing peroxidase in control cells but not in the fibroblasts deficient for NOX4 activity. Our data indicate that DT is a histological marker of IPF and that NOX4 can generate a sufficient amount of H2O2 for DT formation in vitro.

Antifibrotic effects of suramin in injured skeletal muscle after laceration

2003 ◽  
Vol 95 (2) ◽  
pp. 771-780 ◽  
Author(s):  
Yi-Sheng Chan ◽  
Yong Li ◽  
William Foster ◽  
Takashi Horaguchi ◽  
George Somogyi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Regeneration ◽  
Sports Medicine ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Healing Process ◽  
Muscle Injuries

Muscle injuries are very common in traumatology and sports medicine. Although muscle tissue can regenerate postinjury, the healing process is slow and often incomplete; complete recovery after skeletal muscle injury is hindered by fibrosis. Our studies have shown that decreased fibrosis could improve muscle healing. Suramin has been found to inhibit transforming growth factor (TGF)-β1 expression by competitively binding to the growth factor receptor. We conducted a series of tests to determine the antifibrotic effects of suramin on muscle laceration injuries. Our results demonstrate that suramin (50 μg/ml) can effectively decrease fibroblast proliferation and fibrotic-protein expression (α-smooth muscle actin) in vitro. In vivo, direct injection of suramin (2.5 mg) into injured murine muscle resulted in effective inhibition of muscle fibrosis and enhanced muscle regeneration, which led to efficient functional muscle recovery. These results support our hypothesis that prevention of fibrosis could enhance muscle regeneration, thereby facilitating more efficient muscle healing. This study could significantly contribute to the development of strategies to promote efficient muscle healing and functional recovery.

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