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Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs
BACKGROUND: Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflamm...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625853/ https://www.ncbi.nlm.nih.gov/pubmed/26511361 http://dx.doi.org/10.1186/s12931-015-0293-4 |
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author | Freishtat, R J Nino, G Tsegaye, Y Alcala, S E Benton, A S Watson, A M Reeves, E K M Haider, S K Damsker, J M |
author_facet | Freishtat, R J Nino, G Tsegaye, Y Alcala, S E Benton, A S Watson, A M Reeves, E K M Haider, S K Damsker, J M |
author_sort | Freishtat, R J |
collection | PubMed |
description | BACKGROUND: Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells. METHODS: Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-β1, IL-6, IL-10, IL-13, and IL-1β) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry. RESULTS: VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1β) and pro-fibrogenic cytokines (i.e. TGF-β1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury. CONCLUSION: VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions. |
format | Online Article Text |
id | pubmed-4625853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-46258532015-10-30 Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs Freishtat, R J Nino, G Tsegaye, Y Alcala, S E Benton, A S Watson, A M Reeves, E K M Haider, S K Damsker, J M Respir Res Research BACKGROUND: Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells. METHODS: Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-β1, IL-6, IL-10, IL-13, and IL-1β) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry. RESULTS: VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1β) and pro-fibrogenic cytokines (i.e. TGF-β1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury. CONCLUSION: VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions. BioMed Central 2015-10-29 2015 /pmc/articles/PMC4625853/ /pubmed/26511361 http://dx.doi.org/10.1186/s12931-015-0293-4 Text en © Freishtat et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Freishtat, R J Nino, G Tsegaye, Y Alcala, S E Benton, A S Watson, A M Reeves, E K M Haider, S K Damsker, J M Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title | Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title_full | Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title_fullStr | Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title_full_unstemmed | Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title_short | Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
title_sort | pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625853/ https://www.ncbi.nlm.nih.gov/pubmed/26511361 http://dx.doi.org/10.1186/s12931-015-0293-4 |
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