EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice

Jia, Zhirong; Bao, Kaifan; Pan, Wei; Yu, Xuerui; Zhang, Yuheng; Wang, Xiaotong; Lu, Yao; Li, Lianqu; Wu, Peng; Yuan, Weiyuan; Wang, Siqi; Zheng, Jie; Hua, Yongqing

doi:10.1038/s41385-020-0272-z

Cited by 46 publications

(49 citation statements)

References 42 publications

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“…EGFR-ligands binding to EGFR increased Muc5ac production at both gene and protein levels. 31 , 37 H19 was reported to activate EGFR. 38 Consequently, lncRNA H19 probably promotes Muc5ac production through EGFR.…”

Section: Discussionmentioning

confidence: 99%

Muc5ac Production Inhibited by Decreased lncRNA H19 via PI3K/Akt/NF-kB in Asthma

Chen¹,

Yang²,

Shen³

et al. 2021

JAA

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Introduction LncRNAs play important roles in multiple diseases including asthma, while there are a few reports on the role of lncRNA H19 about asthma. This study aimed to investigate the roles and mechanisms of lncRNA H19 in asthma. Methods We detected lncRNA H19 and Muc5ac mRNA by establishing a murine asthma model and an in vitro inflammation model. Regulatory roles of lncRNA H19 in asthma were explored by lncRNA H19 overexpression or knockdown in vitro. To study its mechanisms, we detect p-NF-κB and p-Akt expression, and treated 16-HBE cells with inhibitors of PI3K. To study regulatory effects of miR-675-3p on Muc5ac, miR-675-3p mimics and inhibitors were respectively transfected into 16-HBE cells. Results Firstly, we established a murine asthma model and an in vitro inflammation model. We found that lncRNA H19 expression was decreased, while Muc5ac mRNA was increased in lung tissues of murine asthma model and in the in vitro inflammation model. lncRNA H19 overexpression increased Muc5ac mRNA expression and lncRNA H19 knockdown decreased Muc5ac mRNA expression in 16-HBE cells. Moreover, lncRNA H19 overexpression further increased Muc5ac expression in TNFα-induced in vitro inflammation model. lncRNA H19 knockdown decreased p-Akt and p-NF-κB expression. Inhibitors of PI3K abolished Muc5ac induced by lncRNA H19 overexpression. Although miR-675-3p was increased by lncRNA H19 overexpression, it had no regulatory effects on Muc5ac expression. Discussion These results demonstrated that lncRNA H19 positively regulates Muc5ac expression through PI3K/Akt /NF-κB pathway in the in vitro inflammation model. Therefore, this study indicated that decreased lncRNA H19 in asthma might play a protective role relieving mucus overproduction, and lncRNA H19 might be a potential target for asthma treatment.

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Section: Discussionmentioning

confidence: 99%

Muc5ac Production Inhibited by Decreased lncRNA H19 via PI3K/Akt/NF-kB in Asthma

Chen¹,

Yang²,

Shen³

et al. 2021

JAA

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“…It is known that TIMP-1 binds and inactivates matrix metalloproteinases (MMP), specifically MMP-2 and MMP-9, with imbalances of the MMP-9/TIMP-1 interactions posited in the development of asthma [18][19][20][21]. Additionally, MMP9 activity modulates MUC5AC production via the EGFR pathway [22,23].…”

Section: Discussionmentioning

confidence: 99%

IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma

Mammen

Ali

Aurora

et al. 2021

International Journal of Cell Biology

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Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th1/Th2 response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease.

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“…The key targets were AKT1, IL6, VEGFA, JUN, EGFR, CXCL8, CASP3, MMP9, PTGS2, and MAPK8. Previous research has indicated that AKT1 is related to pathway mechanisms in children with severe asthma [ 33 ]; IL6 polymorphisms are related to the effects of smoking on the risk of adult asthma [ 34 ]; VEGFA rs833069 SNPs are associated with asthma [ 35 ]; VEGFA is associated with the response to inhaled corticosteroids in children with asthma [ 36 ]; smoking aggravates airway inflammation by activating the c -Jun amino terminal kinase pathway in asthma [ 37 ]; EGFR activation-induced decreases in claudin 1 promote MUC5AC expression and exacerbated asthma in mice [ 38 ]; the EGRF-dependent signaling pathway is associated with diseases, such as asthma [ 39 ]; neutrophils release CXCL8, NE, and MMP-9 in response to viral surrogates with R848-induced CXCL8 release being specifically enhanced in neutrophils in asthma [ 40 ]. CASP3 may play a role in allergic asthma [ 41 ]; the PTGS2 gene is associated with diisocyanate-induced asthma [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Strategy to Investigate the Pharmacological Mechanism of HuangQiXiXin Decoction on Cough Variant Asthma and Evidence‐Based Medicine Approach Validation

Xia

Liu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objective. To investigate the pharmacological mechanism of HuangQiXiXin decoction (HQXXD) on cough variant asthma (CVA) and validate the clinical curative effect. Methods. The active compounds and target genes of HQXXD were searched using TCMSP. CVA-related target genes were obtained using the GeneCards database. The active target genes of HQXXD were compared with the CVA-related target genes to identify candidate target genes of HQXXD acting on CVA. A medicine-compound-target network was constructed using Cytoscape 3.6.0 software, and a protein-protein interaction (PPI) network was constructed using the STRING database. Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using RGUI3.6.1 and Cytoscape 3.6.0. We searched the main database for randomized controlled trials of HQXXD for CVA. We assessed the quality of the included studies using the Cochrane Reviewers’ Handbook. A meta-analysis of the clinical curative effect of HQXXD for CVA was conducted using the Cochrane Collaboration’s RevMan 5.3 software. Results. We screened out 48 active compounds and 217 active target genes of HQXXD from TCMSP. The 217 active target genes of HQXXD were compared with the 1481 CVA-related target genes, and 132 candidate target genes for HQXXD acting on CVA were identified. The medicine-compound-target network and PPI network were constructed, and the key compounds and key targets were selected. GO function enrichment and KEGG pathway enrichment analysis were performed. Meta-analysis showed that the total effective rate of the clinical curative effect was significantly higher in the experimental group than the control group. Conclusion. The pharmacological mechanism of HQXXD acting on CVA has been further determined, and the clinical curative effect of HQXXD on CVA is remarkable.

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EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice

Cited by 46 publications

References 42 publications

Muc5ac Production Inhibited by Decreased lncRNA H19 via PI3K/Akt/NF-kB in Asthma

Muc5ac Production Inhibited by Decreased lncRNA H19 via PI3K/Akt/NF-kB in Asthma

IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma

Network Pharmacology Strategy to Investigate the Pharmacological Mechanism of HuangQiXiXin Decoction on Cough Variant Asthma and Evidence‐Based Medicine Approach Validation

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