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 Structural characterization of the latent complex between transforming growth factor β1 and β1-latency-associated peptide

1996 ◽  
Vol 313 (1) ◽  
pp. 343-351 ◽  
Author(s):  
Grainne A. McMAHON ◽  
John D. DIGNAM ◽  
Larry E. GENTRY
Keyword(s):  
Growth Factor ◽  
Cho Cells ◽  
Transforming Growth Factor ◽  
Gel Filtration ◽  
Chinese Hamster ◽  
Transforming Growth Factor Β1 ◽  
Cd Spectroscopy ◽  
Exchange Chromatography ◽  
Lung Epithelial Cells ◽  
Tgf Β1

The formation of a non-covalent complex between mature transforming growth factor β1 (TGF-β1) and its pro region, the β1-latency-associated peptide (β1-LAP), is important in regulating the activity of this multipotent growth factor. We have overexpressed simian β1-LAP in Chinese hamster ovary (CHO) cells to produce a cell line which secretes β1-LAP into the culture medium at > 1 mg/l, thus enabling structural studies of complex formation between β1-LAP and TGF-β1. The simian β1-LAP expressed in CHO cells reversed the growth inhibitory effect of exogenous TGF-β1 on Mv1Lu (mink lung epithelial) cells and was able to form a cross-linked complex with 125I-TGF-β1. Simian β1-LAP was purified to homogeneity by a combination of ammonium sulphate precipitation, gel filtration, dye ligand chromatography and anion-exchange chromatography, with a yield of 15%. The purified protein had an apparent molecular mass of 114 kDa as determined by SDS/PAGE, which is greater than that determined for the transient expression of simian β1-LAP in COS-1 and for the simian precursor of TGF-β1 (pro-TGF-β1) in CHO cells, this major difference being due to more extensive glycosylation of β1-LAP expressed by this CHO clone. Far-UV CD spectroscopy of simian β1-LAP indicates a mostly β-sheet structure, with extensive structural rearrangements occurring upon formation of the latent complex between TGF-β1 and β1-LAP.

Mechanism of Dandelion Sterol in Treating Pulmonary Fibrosis Through Transforming Growth Factor-β Signaling Pathway

2021 ◽  
Vol 11 (4) ◽  
pp. 612-618
Author(s):  
Qun Lv ◽  
Jianjun Wang ◽  
Zhaoyang Ruan
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Level ◽  
Lung Epithelial Cells ◽  
Migration And Invasion ◽  
Lung Epithelial ◽  
Tgf Β1

Background: The paper aimed to elucidate the molecular mechanism of Dandelion sterol in the treatment of pulmonary fibrosis, to study its effect on EMT of lung epithelial cells, and to find its target and downstream signaling pathways. Material and methods: The effects of Dandelion sterol on parathyroid (PQ)-induced EMT in lung epithelial cells were studied by immunofluorescence method. Immunohistochemistry and western-blot methods were used to verify that Dandelion sterol inhibited TGF-β1-induced EMT at the cellular level in animals, demonstrating that Dandelion sterol targets TGF-β1 to exert an anti-pulmonary fibrosis effect. Results: Dandelion sterol significantly inhibited PQ-induced migration and invasion of lung epithelial cells, and also inhibited the induced EMT. Dandelion sterol had a proper binding activity with the lung fibrosis-inducing factor TGF-β1. Dandelion sterol inhibited the TGF-β1-induced EMT process, and acted to treat pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway. Conclusion: Dandelion sterol can inhibit the pulmonary fibrosis by inhibiting the EMT process of lung epithelial cells through targeting the TGF- β1/Smad signaling pathway.

scholarly journals Low-Dose of Intrapulmonary Pirfenidone Improves Human Transforming Growth Factorβ1-Driven Lung Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Tomohito Okano ◽  
Tetsu Kobayashi ◽  
Taro Yasuma ◽  
Corina N. D’Alessandro-Gabazza ◽  
Masaaki Toda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Unknown Etiology ◽  
High Dose ◽  
Dose Oral ◽  
Transforming Growth Factorβ1

Idiopathic pulmonary fibrosis is a chronic, progressive, and lethal lung disease of unknown etiology. Antifibrotic drugs, including pirfenidone, are currently used for the treatment of the disease. The oral administration of pirfenidone is an effective therapy, as demonstrated by several clinical trials, although it causes severe adverse events in some patients. We hypothesized that low-dose intrapulmonary delivery of pirfenidone is effective in human transforming growth factorβ1-driven pulmonary fibrosis. To demonstrate our hypothesis, we compared the therapeutic efficacy of varying doses of pirfenidone administered by oral and intranasal routes in a human transforming growth factor-β1 transgenic mouse with established pulmonary fibrosis. We found similar amelioration of lung cell infiltration, inflammatory and fibrotic cytokines, lung fibrosis score, and hydroxyproline content in mice with human transforming growth factor-β1-mediated pulmonary fibrosis treated with low-dose intranasal pirfenidone and high-dose oral pirfenidone. This study showed that pirfenidone is a potent inhibitor of human transforming growth factor-β1-driven lung fibrosis and that intrapulmonary delivery of low-dose pirfenidone produces therapeutic responses equivalent to high-dose of oral pirfenidone.

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 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 Dermatopontin interacts with transforming growth factor β and enhances its biological activity

1999 ◽  
Vol 337 (3) ◽  
pp. 537-541 ◽  
Author(s):  
Osamu OKAMOTO ◽  
Sakuhei FUJIWARA ◽  
Mayumi ABE ◽  
Yasufumi SATO
Keyword(s):  
Extracellular Matrix ◽  
Biological Activity ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Inhibitory Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Tgf Β1

Dermatopontin, a recently found low-molecular-mass component of the extracellular matrix, was studied for its interaction with decorin and transforming growth factor β (TGF-β) and its influence on TGF-β bioactivity. Dermatopontin reacted with decorin with an apparent Kd of 100 nM in a solid-phase assay. Dermatopontin inhibited the formation of the decorin–TGF-β1 complex. Decorin also competed with dermatopontin for the binding of this cytokine. The dermatopontin–decorin complex bound 3-fold more TGF-β1 than did each component individually, and binding was inhibited more strongly by decorin preincubated with dermatopontin than by dermatopontin or decorin alone. Dermatopontin augmented the biological activity of TGF-β1, as analysed by the expression of luciferase in mink lung epithelial cells transfected with a plasminogen activator inhibitor–promoter–luciferase construct, although dermatopontin itself did not show apparent induction of luciferase. Dermatopontin showed weak inhibitory activity on the proliferation of mink lung epithelial cells, and it enhanced the growth-inhibitory activity of TGF-β on these cells. Thus dermatopontin increases the cellular response to TGF-β. These findings strongly suggest that dermatopontin modifies the behaviour of TGF-β through interaction with decorin in the microenvironment of the extracellular matrix in vivo.

Mechanism of lncRNA H19 in Regulating Pulmonary Injury in Hyperoxia-Induced Bronchopulmonary Dysplasia Newborn Mice

2020 ◽  
Author(s):  
Lina Zhang ◽  
Ping Wang ◽  
Yanhong Shen ◽  
Tao Huang ◽  
Xiaoyun Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bronchopulmonary Dysplasia ◽  
Transforming Growth Factor ◽  
Surfactant Protein ◽  
Transforming Growth Factor Β1 ◽  
Mouse Lung ◽  
Newborn Mouse ◽  
Pulmonary Injury ◽  
Newborn Mice ◽  
Tgf Β1

Objective Bronchopulmonary dysplasia (BPD) is a pulmonary injury related to inflammation and is a major cause of premature infant death. Long noncoding RNAs (lncRNAs) are important regulators in pulmonary injury and inflammation. We investigated the molecular mechanism of lncRNA H19 in pulmonary injury and inflammation in hyperoxia (Hyp)-induced BPD mice. Study Design The BPD newborn mouse model was established and intervened with H19 to evaluate the pathologic conditions and radial alveolar count (RAC) in lung tissues of mice in the room air (RA) and Hyp group on the 4th, 7th, and 14th days after birth. The levels of BPD-related biomarkers vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and surfactant protein C (SPC) in lung tissues were detected on the 14th day after birth. The expression of and relationships among H19 and miR-17, miR-17, and STAT3 were detected and verified. Levels of interleukin (IL)-6, IL-1β, p-STAT3, and STAT3 levels in mouse lung tissues were detected on the 14th day after birth. Results Hyp-induced mice showed increased alveolar diameter, septum, and hyperemia and inflammatory cell infiltration, upregulated H19, decreased overall number and significantly reduced RAC on the 7th and 14th days after birth, which were reversed in the si-H19-treated mice. VEGF was upregulated and TGF-β1 and SPC was decreased in si-H19-treated mice. Moreover, H19 competitively bound to miR-17 to upregulate STAT3. IL-6 and IL-1β expressions and p-STAT3 and STAT3 levels were downregulated after inhibition of H19. Conclusion Downregulated lncRNA H19 relieved pulmonary injury via targeting miR-17 to downregulate STAT3 and reduced inflammatory response caused by p-STAT3 in BPD newborn mice. Key Points

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