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

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 Transforming growth factor-β regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure

2012 ◽  
Vol 302 (9) ◽  
pp. L857-L865 ◽  
Author(s):  
Nelida Olave ◽  
Teodora Nicola ◽  
Wei Zhang ◽  
Arlene Bulger ◽  
Masheika James ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Function ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mouse Lung ◽  
Newborn Mouse ◽  
Newborn Mice ◽  
Endothelin 1 ◽  
Alveolar Development

We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O2) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Transforming growth factor-β1-induced N-cadherin drives cell–cell communication through connexin43 in osteoblast lineage

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yueyi Yang ◽  
Wenjing Liu ◽  
JieYa Wei ◽  
Yujia Cui ◽  
Demao Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gap Junction ◽  
Cell Line ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cx43 Expression ◽  
Mc3t3 Cell ◽  
Primary Osteoblasts ◽  
Tgf Β1 ◽  
Cell Cell

AbstractGap junction (GJ) has been indicated to have an intimate correlation with adhesion junction. However, the direct interaction between them partially remains elusive. In the current study, we aimed to elucidate the role of N-cadherin, one of the core components in adhesion junction, in mediating connexin 43, one of the functional constituents in gap junction, via transforming growth factor-β1(TGF-β1) induction in osteoblasts. We first elucidated the expressions of N-cadherin induced by TGF-β1 and also confirmed the upregulation of Cx43, and the enhancement of functional gap junctional intercellular communication (GJIC) triggered by TGF-β1 in both primary osteoblasts and MC3T3 cell line. Colocalization analysis and Co-IP experimentation showed that N-cadherin interacts with Cx43 at the site of cell–cell contact. Knockdown of N-cadherin by siRNA interference decreased the Cx43 expression and abolished the promoting effect of TGF-β1 on Cx43. Functional GJICs in living primary osteoblasts and MC3T3 cell line were also reduced. TGF-β1-induced increase in N-cadherin and Cx43 was via Smad3 activation, whereas knockdown of Smad3 signaling by using siRNA decreased the expressions of both N-cadherin and Cx43. Overall, these data indicate the direct interactions between N-cadherin and Cx43, and reveal the intervention of adhesion junction in functional gap junction in living osteoblasts.

scholarly journals Transforming Growth Factor β1 (TGF-β1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-α Signaling

2001 ◽  
Vol 21 (21) ◽  
pp. 7218-7230 ◽  
Author(s):  
Francesc Viñals ◽  
Jacques Pouysségur
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Cell Survival ◽  
Network Formation ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vitro Angiogenesis ◽  
Tgf Β1

ABSTRACT Mouse capillary endothelial cells (1G11 cell line) embedded in type I collagen gels undergo in vitro angiogenesis. Cells rapidly reorganize and form capillary-like structures when stimulated with serum. Transforming growth factor β1 (TGF-β1) alone can substitute for serum and induce cell survival and tubular network formation. This TGF-β1-mediated angiogenic activity depends on phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (MAPK) signaling. We showed that specific inhibitors of either pathway (wortmannin, LY-294002, and PD-98059) all suppressed TGF-β1-induced angiogenesis mainly by compromising cell survival. We established that TGF-β1 stimulated the expression of TGF-α mRNA and protein, the tyrosine phosphorylation of a 170-kDa membrane protein representing the epidermal growth factor (EGF) receptor, and the delayed activation of PI3K/Akt and p42/p44 MAPK. Moreover, we showed that all these TGF-β1-mediated signaling events, including tubular network formation, were suppressed by incubating TGF-β1-stimulated endothelial cells with a soluble form of an EGF receptor (ErbB-1) or tyrphostin AG1478, a specific blocker of EGF receptor tyrosine kinase. Finally, addition of TGF-α alone poorly stimulated angiogenesis; however, by reducing cell death, it strongly potentiated the action of TGF-β1. We therefore propose that TGF-β1 promotes angiogenesis at least in part via the autocrine secretion of TGF-α, a cell survival growth factor, activating PI3K/Akt and p42/p44 MAPK.

scholarly journals Transforming Growth Factor β1 (TGF-β1) Suppresses Growth of B-cell Lymphoma Cells by p14ARF-dependent Regulation of Mutant p53

2012 ◽  
Vol 287 (27) ◽  
pp. 23184-23195 ◽  
Author(s):  
Gang Chen ◽  
Paritosh Ghosh ◽  
Thomas O'Farrell ◽  
Rachel Munk ◽  
Louis J. Rezanka ◽  
...  
Keyword(s):  
Growth Factor ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Transforming Growth Factor Β1 ◽  
Mutant P53 ◽  
Lymphoma Cells ◽  
Tgf Β1
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