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Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse
BACKGROUND: It has been proposed that serotonin (5-HT)-mediated constriction of the murine trachea is largely dependent on acetylcholine (ACh) released from the epithelium. We recently demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cati...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2006
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1468398/ https://www.ncbi.nlm.nih.gov/pubmed/16608531 http://dx.doi.org/10.1186/1465-9921-7-65 |
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author | Kummer, Wolfgang Wiegand, Silke Akinci, Sibel Wessler, Ignatz Schinkel, Alfred H Wess, Jürgen Koepsell, Hermann Haberberger, Rainer V Lips, Katrin S |
author_facet | Kummer, Wolfgang Wiegand, Silke Akinci, Sibel Wessler, Ignatz Schinkel, Alfred H Wess, Jürgen Koepsell, Hermann Haberberger, Rainer V Lips, Katrin S |
author_sort | Kummer, Wolfgang |
collection | PubMed |
description | BACKGROUND: It has been proposed that serotonin (5-HT)-mediated constriction of the murine trachea is largely dependent on acetylcholine (ACh) released from the epithelium. We recently demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells. Hence, the hypothesis emerged that 5-HT evokes bronchoconstriction by inducing release of ACh from epithelial cells via OCTs. METHODS: We tested this hypothesis by analysing bronchoconstriction in precision-cut murine lung slices using OCT and muscarinic ACh receptor knockout mouse strains. Epithelial ACh content was measured by HPLC, and the tissue distribution of OCT isoforms was determined by immunohistochemistry. RESULTS: Epithelial ACh content was significantly higher in OCT1/2 double-knockout mice (42 ± 10 % of the content of the epithelium-denuded trachea, n = 9) than in wild-type mice (16.8 ± 3.6 %, n = 11). In wild-type mice, 5-HT (1 μM) caused a bronchoconstriction that slightly exceeded that evoked by muscarine (1 μM) in intact bronchi but amounted to only 66% of the response to muscarine after epithelium removal. 5-HT-induced bronchoconstriction was undiminished in M(2)/M(3 )muscarinic ACh receptor double-knockout mice which were entirely unresponsive to muscarine. Corticosterone (1 μM) significantly reduced 5-HT-induced bronchoconstriction in wild-type and OCT1/2 double-knockout mice, but not in OCT3 knockout mice. This effect persisted after removal of the bronchial epithelium. Immunohistochemistry localized OCT3 to the bronchial smooth muscle. CONCLUSION: The doubling of airway epithelial ACh content in OCT1/2(-/- )mice is consistent with the concept that OCT1 and/or 2 mediate ACh release from the respiratory epithelium. This effect, however, does not contribute to 5-HT-induced constriction of murine intrapulmonary bronchi. Instead, this activity involves 1) a non-cholinergic epithelium-dependent component, and 2) direct stimulation of bronchial smooth muscle cells, a response which is partly sensitive to acutely administered corticosterone acting on OCT3. These data provide new insights into the mechanisms involved in 5-HT-induced bronchoconstriction, including novel information about non-genomic, acute effects of corticosteroids on bronchoconstriction. |
format | Text |
id | pubmed-1468398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-14683982006-05-25 Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse Kummer, Wolfgang Wiegand, Silke Akinci, Sibel Wessler, Ignatz Schinkel, Alfred H Wess, Jürgen Koepsell, Hermann Haberberger, Rainer V Lips, Katrin S Respir Res Research BACKGROUND: It has been proposed that serotonin (5-HT)-mediated constriction of the murine trachea is largely dependent on acetylcholine (ACh) released from the epithelium. We recently demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells. Hence, the hypothesis emerged that 5-HT evokes bronchoconstriction by inducing release of ACh from epithelial cells via OCTs. METHODS: We tested this hypothesis by analysing bronchoconstriction in precision-cut murine lung slices using OCT and muscarinic ACh receptor knockout mouse strains. Epithelial ACh content was measured by HPLC, and the tissue distribution of OCT isoforms was determined by immunohistochemistry. RESULTS: Epithelial ACh content was significantly higher in OCT1/2 double-knockout mice (42 ± 10 % of the content of the epithelium-denuded trachea, n = 9) than in wild-type mice (16.8 ± 3.6 %, n = 11). In wild-type mice, 5-HT (1 μM) caused a bronchoconstriction that slightly exceeded that evoked by muscarine (1 μM) in intact bronchi but amounted to only 66% of the response to muscarine after epithelium removal. 5-HT-induced bronchoconstriction was undiminished in M(2)/M(3 )muscarinic ACh receptor double-knockout mice which were entirely unresponsive to muscarine. Corticosterone (1 μM) significantly reduced 5-HT-induced bronchoconstriction in wild-type and OCT1/2 double-knockout mice, but not in OCT3 knockout mice. This effect persisted after removal of the bronchial epithelium. Immunohistochemistry localized OCT3 to the bronchial smooth muscle. CONCLUSION: The doubling of airway epithelial ACh content in OCT1/2(-/- )mice is consistent with the concept that OCT1 and/or 2 mediate ACh release from the respiratory epithelium. This effect, however, does not contribute to 5-HT-induced constriction of murine intrapulmonary bronchi. Instead, this activity involves 1) a non-cholinergic epithelium-dependent component, and 2) direct stimulation of bronchial smooth muscle cells, a response which is partly sensitive to acutely administered corticosterone acting on OCT3. These data provide new insights into the mechanisms involved in 5-HT-induced bronchoconstriction, including novel information about non-genomic, acute effects of corticosteroids on bronchoconstriction. BioMed Central 2006 2006-04-12 /pmc/articles/PMC1468398/ /pubmed/16608531 http://dx.doi.org/10.1186/1465-9921-7-65 Text en Copyright © 2006 Kummer et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Kummer, Wolfgang Wiegand, Silke Akinci, Sibel Wessler, Ignatz Schinkel, Alfred H Wess, Jürgen Koepsell, Hermann Haberberger, Rainer V Lips, Katrin S Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title | Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title_full | Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title_fullStr | Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title_full_unstemmed | Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title_short | Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
title_sort | role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1468398/ https://www.ncbi.nlm.nih.gov/pubmed/16608531 http://dx.doi.org/10.1186/1465-9921-7-65 |
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