Bronchopulmonary Dysplasia: Crosstalk Between PPARγ, WNT/β-Catenin and TGF-β Pathways; The Potential Therapeutic Role of PPARγ Agonists

Lecarpentier, Yves; Gourrier, Elizabeth; Gobert, Vincent; Vallée, Alexandre

doi:10.3389/fped.2019.00176

Cited by 33 publications

(33 citation statements)

References 196 publications

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“…The foregoing results indicate that miR‐342‐5p mimic therapy serves to correct lung epithelial Raf1/ERK1/2 signalling dysregulation within BPD mice post‐hyperoxia. Hyperoxia‐induced neonatal lung injury is mediated via TGFβ activation (Lecarpentier et al, 2019). Moreover, TGFβ1‐induced epithelial–mesenchymal transitioning in T2AECs, which leads to myofibroblast differentiation and lung fibrosis, has previously been shown to be inhibited by ERK1/2 signalling (Watanabe‐Takano et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

Wen

Zhang

Xiang

et al. 2021

British J Pharmacology

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Background and Purpose Bronchopulmonary dysplasia (BPD) is the most prevalent chronic paediatric lung disease and is linked to the development of chronic obstructive pulmonary disease. MicroRNA‐based regulation of type II alveolar epithelial cell (T2AEC) proliferation and apoptosis is an important factor in the pathogenesis of BPD and warrants further investigation. Experimental Approach Two murine models of hyperoxic lung injury (with or without miR‐342‐5p or Sprouty‐related, EVH1 domain‐containing protein 3 [Spred3] modulation) were employed: a hyperoxia‐induced acute lung injury model (100% O2 on postnatal days 1–7) and the BPD model (100% O2 on postnatal days 1–4, followed by room air for 10 days). Tracheal aspirate pellets from healthy control and moderate/severe BPD neonates were randomly selected for clinical miR‐342‐5p analysis. Key Results Hyperoxia decreased miR‐342‐5p levels in primary T2AECs, MLE12 cells and neonatal mouse lungs. Transgenic miR‐342 overexpression in neonatal mice ameliorated survival rates and improved the BPD phenotype and BPD‐associated pulmonary arterial hypertension (PAH). T2AEC‐specific miR‐342 transgenic overexpression, as well as miR‐342‐5p mimic therapy, also ameliorated the BPD phenotype and associated PAH. miR‐342‐5p targets the 3′UTR of the Raf1 regulator Spred3, inhibiting Spred3 expression. Treatment with recombinant Spred3 exacerbated the BPD phenotype and associated PAH. Notably, miR‐342‐5p inhibition under room air conditions did not mimic the BPD phenotype. Moderate/severe BPD tracheal aspirate pellets exhibited decreased miR‐342‐5p levels relative to healthy control pellets. Conclusion and Implications These findings suggest that miR‐342‐5p mimic therapy may show promise in the treatment or prevention of BPD.

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Section: Resultsmentioning

confidence: 99%

Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

Wen

Zhang

Xiang

et al. 2021

British J Pharmacology

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“…TGF-β cooperates with Wnt/β-catenin to forward complete EMT and regulate the mesenchymal phenotype of invasive/metastatic tumor cells 57 . TGF-β can upregulate canonical Wnt signaling 58 . TGF-β1 induced β-catenin nuclear translocation in primary porcine valve interstitial cells through TGF-β receptor I kinase 59 .…”

Section: Discussionmentioning

confidence: 99%

β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis

Yoo

Kim

et al. 2020

Exp Mol Med

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Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma within the myometrium. Adenomyosis is a common cause of dysmenorrhea, menorrhagia, and chronic pelvic pain but is often underdiagnosed. Despite its prevalence and severity of symptoms, its pathogenesis and etiology are poorly understood. Our previous study showed that aberrant activation of β-catenin results in adenomyosis through epithelial–mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-β signaling in the uteri of mutant mice that expressed dominant stabilized β-catenin in the uterus. There was a strong positive correlation between β-catenin and TGF-β2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-β inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear β-catenin. Our results suggest that β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-β as a potential therapeutic target for adenomyosis.

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“…Disruption of this process results in trans-differentiation of lung alveolar lipofibroblasts to myofibroblasts, contributing to the development of pulmonary fibrosis [ 84 , 85 ]. Importantly, PPARG agonists have been suggested as therapeutic targets for BPD due to their implications in the Wnt/β-catenin and TGF-β pathways [ 86 ]. Both pathways are induced by hypoxia, leading to decreased levels of PPARG and the subsequent differentiation of fibroblasts, leading to pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Signatures Associated with Bronchopulmonary Dysplasia Severity in Tracheal Aspirates of Preterm Infants

et al. 2021

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Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth, arrested fetal lung development, and inflammation. The incidence of BPD remains on the rise as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of BPD severity. We collected tracheal aspirates (TAs) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, false discovery rate (FDR) < 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD group when compared to the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extremely premature infants contain miRNA signatures associated with severe BPD. These may serve as potential biomarkers of disease severity in infants with BPD.

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Bronchopulmonary Dysplasia: Crosstalk Between PPARγ, WNT/β-Catenin and TGF-β Pathways; The Potential Therapeutic Role of PPARγ Agonists

Cited by 33 publications

References 196 publications

Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis

MicroRNA Signatures Associated with Bronchopulmonary Dysplasia Severity in Tracheal Aspirates of Preterm Infants

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