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PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model
BACKGROUND: Tyrosine kinase and phosphoinositide kinase pathways play important roles in asthma formation. As a dual tyrosine and phosphoinositide kinase inhibitor, PP121 has shown anticancer efficacy in multiple tumors. However, the study of PP121 in pulmonary diseases is still limited. Herein, we...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629066/ https://www.ncbi.nlm.nih.gov/pubmed/37936054 http://dx.doi.org/10.1186/s10020-023-00748-w |
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author | Li, Wei Xue, Lu Peng, Changsi Zhao, Ping Peng, Yongbo Chen, Weiwei Wang, Wenyi Shen, Jinhua |
author_facet | Li, Wei Xue, Lu Peng, Changsi Zhao, Ping Peng, Yongbo Chen, Weiwei Wang, Wenyi Shen, Jinhua |
author_sort | Li, Wei |
collection | PubMed |
description | BACKGROUND: Tyrosine kinase and phosphoinositide kinase pathways play important roles in asthma formation. As a dual tyrosine and phosphoinositide kinase inhibitor, PP121 has shown anticancer efficacy in multiple tumors. However, the study of PP121 in pulmonary diseases is still limited. Herein, we investigated the therapeutic activities of PP121 in asthma treatment. METHODS: Tension measurements and patch clamp recordings were made to investigate the anticontractile characteristics of PP121 in vitro. Then, an asthma mouse model was established to further explore the therapeutic characteristics of PP121 via measurement of respiratory system resistance, histological analysis and western blotting. RESULTS: We discovered that PP121 could relax precontracted mouse tracheal rings (mTRs) by blocking certain ion channels, including L-type voltage-dependent Ca(2+) channels (L-VDCCs), nonselective cation channels (NSCCs), transient receptor potential channels (TRPCs), Na(+)/Ca(2+) exchangers (NCXs) and K(+) channels, and accelerating calcium mobilization. Furthermore, PP121 relieved asthmatic pathological features, including airway hyperresponsiveness, systematic inflammation and mucus secretion, via downregulation of inflammatory factors, mucins and the mitogen-activated protein kinase (MAPK)/Akt signaling pathway in asthmatic mice. CONCLUSION: In summary, PP121 exerts dual anti-contractile and anti-inflammatory effects in asthma treatment, which suggests that PP121 might be a promising therapeutic compound and shed new light on asthma therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00748-w. |
format | Online Article Text |
id | pubmed-10629066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106290662023-11-08 PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model Li, Wei Xue, Lu Peng, Changsi Zhao, Ping Peng, Yongbo Chen, Weiwei Wang, Wenyi Shen, Jinhua Mol Med Research Article BACKGROUND: Tyrosine kinase and phosphoinositide kinase pathways play important roles in asthma formation. As a dual tyrosine and phosphoinositide kinase inhibitor, PP121 has shown anticancer efficacy in multiple tumors. However, the study of PP121 in pulmonary diseases is still limited. Herein, we investigated the therapeutic activities of PP121 in asthma treatment. METHODS: Tension measurements and patch clamp recordings were made to investigate the anticontractile characteristics of PP121 in vitro. Then, an asthma mouse model was established to further explore the therapeutic characteristics of PP121 via measurement of respiratory system resistance, histological analysis and western blotting. RESULTS: We discovered that PP121 could relax precontracted mouse tracheal rings (mTRs) by blocking certain ion channels, including L-type voltage-dependent Ca(2+) channels (L-VDCCs), nonselective cation channels (NSCCs), transient receptor potential channels (TRPCs), Na(+)/Ca(2+) exchangers (NCXs) and K(+) channels, and accelerating calcium mobilization. Furthermore, PP121 relieved asthmatic pathological features, including airway hyperresponsiveness, systematic inflammation and mucus secretion, via downregulation of inflammatory factors, mucins and the mitogen-activated protein kinase (MAPK)/Akt signaling pathway in asthmatic mice. CONCLUSION: In summary, PP121 exerts dual anti-contractile and anti-inflammatory effects in asthma treatment, which suggests that PP121 might be a promising therapeutic compound and shed new light on asthma therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00748-w. BioMed Central 2023-11-07 /pmc/articles/PMC10629066/ /pubmed/37936054 http://dx.doi.org/10.1186/s10020-023-00748-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Li, Wei Xue, Lu Peng, Changsi Zhao, Ping Peng, Yongbo Chen, Weiwei Wang, Wenyi Shen, Jinhua PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title | PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title_full | PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title_fullStr | PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title_full_unstemmed | PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title_short | PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
title_sort | pp121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629066/ https://www.ncbi.nlm.nih.gov/pubmed/37936054 http://dx.doi.org/10.1186/s10020-023-00748-w |
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