RETRACTED: Targeted inhibition of Six1 attenuates allergic airway inflammation and remodeling in asthmatic mice

Yang, Zhaochuan; Man, Yi; Shan, Yanchun; Wang, Chong; Ni, Ran; Jin, Lina; Fu, Peng; Feng, Xia; Xu, Lei; Qu, Zhenghai

doi:10.1016/j.biopha.2016.10.090

Cited by 17 publications

(18 citation statements)

References 22 publications

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“…The results of the current study together with our prior observations on the expression of Six1 in the bronchoalveolar lavage fluid of children with asthma and lung tissue of a mouse model of asthma [4] show that Six1 plays a necessary role in the process of airway remodelling in asthma. Our studies have demonstrated that Six1 can promote EMT in bronchial epithelial cells via the TGFβ1/ Smad signalling pathway, which is critical for fibrosis and remodelling of the airway wall.…”

Section: Discussionsupporting

confidence: 76%

“…Its contribution to carcinogenesis has been described in several malignancies and diseases, such as lung cancer and pulmonary fibrosis [2,3]. In our previous studies, we demonstrated that the expression of Six1 was increased significantly in the bronchoalveolar lavage fluid from children with asthma and lung tissue of a mouse model of asthma induced by OVA compared with the respective normal controls, while downregulation of Six1 inhibited airway inflammation and reversed airway remodelling in a mouse model of asthma [4]. It has been confirmed that Six1 plays a certain role in the pathogenesis of asthma, but the molecular mechanism of Six1 in airway remodelling in asthma is still unclear.…”

Section: Introductionmentioning

confidence: 77%

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Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

Wang

Yang

et al. 2021

Int Arch Allergy Immunol

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Introduction: The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism. Methods: A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFβ1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot. Results: Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFβ1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFβ1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFβ1/Smad signalling pathway, which could be reduced by a TGFβ1 inhibitor. Conclusion: These data reveal that Six1 and TGFβ1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFβ1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 77%

Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

Wang

Yang

et al. 2021

Int Arch Allergy Immunol

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“…However, whether the expression of MMP-2 is detrimental or protective in early stages of allergic airway inflammation is unclear. There are studies showing high, low or unchanged expression level of MMP-2 in asthmatic conditions compared to control (19–25).…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Matrix Metalloproteinase-2 in Allergic Bronchial Asthma

et al. 2019

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Inflammation, reversible obstruction, and hyperresponsiveness of the airways are characteristic findings of bronchial asthma. Several evidence has demonstrated the involvement of matrix metalloproteinase-2 in allergic airway inflammation. Matrix metalloproteinase-2 may promote aberrant tissue remodeling in late stages of allergic airway inflammation. However, whether matrix metalloproteinase-2 is detrimental or protective in early stages of allergic airway inflammation remains unclear. To evaluate this here we compared the severity of allergic bronchial asthma between mice overexpressing human matrix metalloproteinase-2 and wild type mice. After sensitization and challenge with an allergen, mice overexpressing the human matrix metalloproteinase-2 showed a significant reduction in airway hyperresponsiveness and in the expression of Th2 cytokines and IgE compared to their wild type counterparts. An inhibitor of matrix metalloproteinases abolished this beneficial effect of human matrix metalloproteinase-2 overexpression. Allergen-sensitized and challenged human matrix metalloproteinase-2 transgenic mice had enhanced percentage of M1 macrophages with increased expression of inducible nitric oxide synthase and STAT1 activation in the lungs compared to their wild type counterparts. There was no difference in the percentage of regulatory T cells between mouse groups. The results of this study showed that matrix metalloproteinase-2 is protective in allergic bronchial asthma by promoting polarization of macrophages to M1 phenotype.

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“…These enriched areas are thought to aggregate in response to resident cellular injury—such as that found in BLM‐induced lung inflammation—leading to PH and fibrosis dependent in large part upon proliferation of various effector T‐cell populations (Jun et al, 2011). T regulatory cell induction, however, reduces lung inflammation, fibrosis, and cardiac dysfunction in response to prolonged insult (Yang et al, 2016).…”

Section: Inflammationmentioning

confidence: 99%

Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra

Rajagopal

Bryant

Sahay

et al. 2020

British J Pharmacology

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Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where the additional presence of pulmonary hypertension (PH) reduces survival. In particular, the presence of coexistent pulmonary vascular disease in patients with advanced lung parenchymal disease results in worse outcomes than either diagnosis alone. This is true with respect to the natural histories of these diseases, outcomes with medical therapies, and even outcomes following lung transplantation. Consequently, there is a striking need for improved treatments for PH in the setting of IPF. In this review, we summarize existing therapies from the perspective of molecular mechanisms underlying lung fibrosis and vasoconstriction/vascular remodelling and discuss potential future targets for pharmacotherapy.

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RETRACTED: Targeted inhibition of Six1 attenuates allergic airway inflammation and remodeling in asthmatic mice

Cited by 17 publications

References 22 publications

Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

Protective Role of Matrix Metalloproteinase-2 in Allergic Bronchial Asthma

Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra

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