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Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium

BACKGROUND: Mucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (L...

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Autores principales: Katsumata, Mineo, Fujisawa, Tomoyuki, Kamiya, Yosuke, Tanaka, Yuko, Kamiya, Chiaki, Inoue, Yusuke, Hozumi, Hironao, Karayama, Masato, Suzuki, Yuzo, Furuhashi, Kazuki, Enomoto, Noriyuki, Nakamura, Yutaro, Inui, Naoki, Maekawa, Masato, Setou, Mitsutoshi, Watanabe, Hiroshi, Ikegami, Koji, Suda, Takafumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9080152/
https://www.ncbi.nlm.nih.gov/pubmed/35527239
http://dx.doi.org/10.1186/s12890-022-01983-3
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author Katsumata, Mineo
Fujisawa, Tomoyuki
Kamiya, Yosuke
Tanaka, Yuko
Kamiya, Chiaki
Inoue, Yusuke
Hozumi, Hironao
Karayama, Masato
Suzuki, Yuzo
Furuhashi, Kazuki
Enomoto, Noriyuki
Nakamura, Yutaro
Inui, Naoki
Maekawa, Masato
Setou, Mitsutoshi
Watanabe, Hiroshi
Ikegami, Koji
Suda, Takafumi
author_facet Katsumata, Mineo
Fujisawa, Tomoyuki
Kamiya, Yosuke
Tanaka, Yuko
Kamiya, Chiaki
Inoue, Yusuke
Hozumi, Hironao
Karayama, Masato
Suzuki, Yuzo
Furuhashi, Kazuki
Enomoto, Noriyuki
Nakamura, Yutaro
Inui, Naoki
Maekawa, Masato
Setou, Mitsutoshi
Watanabe, Hiroshi
Ikegami, Koji
Suda, Takafumi
author_sort Katsumata, Mineo
collection PubMed
description BACKGROUND: Mucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions. METHODS: Wild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed. RESULTS: Intranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration. CONCLUSIONS: LAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12890-022-01983-3.
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spelling pubmed-90801522022-05-09 Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium Katsumata, Mineo Fujisawa, Tomoyuki Kamiya, Yosuke Tanaka, Yuko Kamiya, Chiaki Inoue, Yusuke Hozumi, Hironao Karayama, Masato Suzuki, Yuzo Furuhashi, Kazuki Enomoto, Noriyuki Nakamura, Yutaro Inui, Naoki Maekawa, Masato Setou, Mitsutoshi Watanabe, Hiroshi Ikegami, Koji Suda, Takafumi BMC Pulm Med Research BACKGROUND: Mucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions. METHODS: Wild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed. RESULTS: Intranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration. CONCLUSIONS: LAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12890-022-01983-3. BioMed Central 2022-05-08 /pmc/articles/PMC9080152/ /pubmed/35527239 http://dx.doi.org/10.1186/s12890-022-01983-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Katsumata, Mineo
Fujisawa, Tomoyuki
Kamiya, Yosuke
Tanaka, Yuko
Kamiya, Chiaki
Inoue, Yusuke
Hozumi, Hironao
Karayama, Masato
Suzuki, Yuzo
Furuhashi, Kazuki
Enomoto, Noriyuki
Nakamura, Yutaro
Inui, Naoki
Maekawa, Masato
Setou, Mitsutoshi
Watanabe, Hiroshi
Ikegami, Koji
Suda, Takafumi
Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title_full Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title_fullStr Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title_full_unstemmed Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title_short Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
title_sort effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9080152/
https://www.ncbi.nlm.nih.gov/pubmed/35527239
http://dx.doi.org/10.1186/s12890-022-01983-3
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