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Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation

INTRODUCTION: Despite recent advances, there are limited treatments available for acute asthma exacerbations. Here, we investigated the therapeutic potential of GGsTop, a γ-glutamyl transferase inhibitor, on the disease with a murine model of asthma exacerbation. METHODS: GGsTop was administered to...

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Autores principales: Zhang, Cancan, Xu, Huisha, Netto, Keilah G., Sokulsky, Leon A., Miao, Yiyan, Mo, Zhongyuan, Meng, Yan, Du, Yingying, Wu, Chengyong, Han, Liyou, Zhang, Lirong, Liu, Chi, Zhang, Guojun, Li, Fuguang, Yang, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10292800/
https://www.ncbi.nlm.nih.gov/pubmed/37377967
http://dx.doi.org/10.3389/fimmu.2023.1132939
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author Zhang, Cancan
Xu, Huisha
Netto, Keilah G.
Sokulsky, Leon A.
Miao, Yiyan
Mo, Zhongyuan
Meng, Yan
Du, Yingying
Wu, Chengyong
Han, Liyou
Zhang, Lirong
Liu, Chi
Zhang, Guojun
Li, Fuguang
Yang, Ming
author_facet Zhang, Cancan
Xu, Huisha
Netto, Keilah G.
Sokulsky, Leon A.
Miao, Yiyan
Mo, Zhongyuan
Meng, Yan
Du, Yingying
Wu, Chengyong
Han, Liyou
Zhang, Lirong
Liu, Chi
Zhang, Guojun
Li, Fuguang
Yang, Ming
author_sort Zhang, Cancan
collection PubMed
description INTRODUCTION: Despite recent advances, there are limited treatments available for acute asthma exacerbations. Here, we investigated the therapeutic potential of GGsTop, a γ-glutamyl transferase inhibitor, on the disease with a murine model of asthma exacerbation. METHODS: GGsTop was administered to mice that received lipopolysaccharide (LPS) and ovalbumin (OVA) challenges. Airway hyperresponsiveness (AHR), lung histology, mucus hypersecretion, and collagen deposition were analyzed to evaluate the hallmark features of asthma exacerbation. The level of proinflammatory cytokines and glutathione were determined with/without GGsTop. The transcription profiles were also examined. RESULTS: GGsTop attenuates hallmark features of the disease with a murine model of LPS and OVA driven asthma exacerbation. Airway hyperresponsiveness (AHR), mucus hypersecretion, collagen deposition, and expression of inflammatory cytokines were dramatically inhibited by GGsTop treatment. Additionally, GGsTop restored the level of glutathione. Using RNA-sequencing and pathway analysis, we demonstrated that the activation of LPS/NFκB signaling pathway in airway was downregulated by GGsTop. Interestingly, further analysis revealed that GGsTop significantly inhibited not only IFNγ responses but also the expression of glucocorticoid-associated molecules, implicating that GGsTop profoundly attenuates inflammatory pathways. CONCLUSIONS: Our study suggests that GGsTop is a viable treatment for asthma exacerbation by broadly inhibiting the activation of multiple inflammatory pathways.
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spelling pubmed-102928002023-06-27 Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation Zhang, Cancan Xu, Huisha Netto, Keilah G. Sokulsky, Leon A. Miao, Yiyan Mo, Zhongyuan Meng, Yan Du, Yingying Wu, Chengyong Han, Liyou Zhang, Lirong Liu, Chi Zhang, Guojun Li, Fuguang Yang, Ming Front Immunol Immunology INTRODUCTION: Despite recent advances, there are limited treatments available for acute asthma exacerbations. Here, we investigated the therapeutic potential of GGsTop, a γ-glutamyl transferase inhibitor, on the disease with a murine model of asthma exacerbation. METHODS: GGsTop was administered to mice that received lipopolysaccharide (LPS) and ovalbumin (OVA) challenges. Airway hyperresponsiveness (AHR), lung histology, mucus hypersecretion, and collagen deposition were analyzed to evaluate the hallmark features of asthma exacerbation. The level of proinflammatory cytokines and glutathione were determined with/without GGsTop. The transcription profiles were also examined. RESULTS: GGsTop attenuates hallmark features of the disease with a murine model of LPS and OVA driven asthma exacerbation. Airway hyperresponsiveness (AHR), mucus hypersecretion, collagen deposition, and expression of inflammatory cytokines were dramatically inhibited by GGsTop treatment. Additionally, GGsTop restored the level of glutathione. Using RNA-sequencing and pathway analysis, we demonstrated that the activation of LPS/NFκB signaling pathway in airway was downregulated by GGsTop. Interestingly, further analysis revealed that GGsTop significantly inhibited not only IFNγ responses but also the expression of glucocorticoid-associated molecules, implicating that GGsTop profoundly attenuates inflammatory pathways. CONCLUSIONS: Our study suggests that GGsTop is a viable treatment for asthma exacerbation by broadly inhibiting the activation of multiple inflammatory pathways. Frontiers Media S.A. 2023-06-12 /pmc/articles/PMC10292800/ /pubmed/37377967 http://dx.doi.org/10.3389/fimmu.2023.1132939 Text en Copyright © 2023 Zhang, Xu, Netto, Sokulsky, Miao, Mo, Meng, Du, Wu, Han, Zhang, Liu, Zhang, Li and Yang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhang, Cancan
Xu, Huisha
Netto, Keilah G.
Sokulsky, Leon A.
Miao, Yiyan
Mo, Zhongyuan
Meng, Yan
Du, Yingying
Wu, Chengyong
Han, Liyou
Zhang, Lirong
Liu, Chi
Zhang, Guojun
Li, Fuguang
Yang, Ming
Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title_full Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title_fullStr Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title_full_unstemmed Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title_short Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
title_sort inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10292800/
https://www.ncbi.nlm.nih.gov/pubmed/37377967
http://dx.doi.org/10.3389/fimmu.2023.1132939
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