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Effects of 5-Hydroxytryptamine Class 2 Receptor Antagonists on Bronchoconstriction and Pulmonary Remodeling Processes

Löfdahl, Anna LU ; Wenglén, Christina LU ; Rydell-Törmänen, Kristina LU ; Westergren-Thorsson, Gunilla LU and Larsson-Callerfelt, Anna Karin LU (2018) In American Journal of Pathology 188(5). p.1113-1119
Abstract

Serotonin [5-hydroxytryptamine (5-HT)] is associated with several chronic pulmonary diseases, recognizing 5-HT2 receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT2 receptors, especially 5-HT2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pretreated with 5-HT2B receptor antagonists (EXT5, EXT9, RS 127445, and PRX 08066), as well as ketanserin (5-HT2A/2C receptor antagonist) (1, 10 μmol/L), before addition of cumulative concentrations of 5-HT to induce bronchoconstriction.... (More)

Serotonin [5-hydroxytryptamine (5-HT)] is associated with several chronic pulmonary diseases, recognizing 5-HT2 receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT2 receptors, especially 5-HT2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pretreated with 5-HT2B receptor antagonists (EXT5, EXT9, RS 127445, and PRX 08066), as well as ketanserin (5-HT2A/2C receptor antagonist) (1, 10 μmol/L), before addition of cumulative concentrations of 5-HT to induce bronchoconstriction. Remodeling effects after treatment with 10 μmol/L 5-HT and 5-HT2 receptor antagonists were further studied in distal lung tissue by examining release of profibrotic transforming growth factor (TGF)-β1 and proliferation of human bronchial smooth muscle cells (HBSMCs). 5-HT–induced bronchoconstriction was significantly reduced by EXT5, EXT9, and ketanserin, but not by RS 127445 or PRX 08066. The 5-HT2B receptor antagonists significantly reduced TGF-β1 release. 5-HT, in combination with TGF-β1, increased proliferation of HBSMCs, a process reduced by EXT5 and EXT9. Our results indicate that EXT5 and EXT9 may relieve bronchoconstriction in murine airways and serve as an add-on effect in attenuating pulmonary remodeling by improving airway function. The antiproliferative effect on HBSMCs and the inhibition of TGF-β1 release further support a role of 5-HT2B receptors in pathologic remodeling processes.

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type
Contribution to journal
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published
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in
American Journal of Pathology
volume
188
issue
5
pages
7 pages
publisher
American Society for Investigative Pathology
external identifiers
  • scopus:85045031213
  • pmid:29454752
ISSN
0002-9440
DOI
10.1016/j.ajpath.2018.01.006
language
English
LU publication?
yes
id
c42f3470-5199-4383-9bc4-6f93fac4446e
date added to LUP
2018-04-17 13:44:39
date last changed
2020-11-10 04:32:47
@article{c42f3470-5199-4383-9bc4-6f93fac4446e,
  abstract     = {<p>Serotonin [5-hydroxytryptamine (5-HT)] is associated with several chronic pulmonary diseases, recognizing 5-HT<sub>2</sub> receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT<sub>2</sub> receptors, especially 5-HT<sub>2B</sub> receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT<sub>2B</sub> receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pretreated with 5-HT<sub>2B</sub> receptor antagonists (EXT5, EXT9, RS 127445, and PRX 08066), as well as ketanserin (5-HT<sub>2A/2C</sub> receptor antagonist) (1, 10 μmol/L), before addition of cumulative concentrations of 5-HT to induce bronchoconstriction. Remodeling effects after treatment with 10 μmol/L 5-HT and 5-HT<sub>2</sub> receptor antagonists were further studied in distal lung tissue by examining release of profibrotic transforming growth factor (TGF)-β1 and proliferation of human bronchial smooth muscle cells (HBSMCs). 5-HT–induced bronchoconstriction was significantly reduced by EXT5, EXT9, and ketanserin, but not by RS 127445 or PRX 08066. The 5-HT<sub>2B</sub> receptor antagonists significantly reduced TGF-β1 release. 5-HT, in combination with TGF-β1, increased proliferation of HBSMCs, a process reduced by EXT5 and EXT9. Our results indicate that EXT5 and EXT9 may relieve bronchoconstriction in murine airways and serve as an add-on effect in attenuating pulmonary remodeling by improving airway function. The antiproliferative effect on HBSMCs and the inhibition of TGF-β1 release further support a role of 5-HT<sub>2B</sub> receptors in pathologic remodeling processes.</p>},
  author       = {Löfdahl, Anna and Wenglén, Christina and Rydell-Törmänen, Kristina and Westergren-Thorsson, Gunilla and Larsson-Callerfelt, Anna Karin},
  issn         = {0002-9440},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {1113--1119},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Effects of 5-Hydroxytryptamine Class 2 Receptor Antagonists on Bronchoconstriction and Pulmonary Remodeling Processes},
  url          = {http://dx.doi.org/10.1016/j.ajpath.2018.01.006},
  doi          = {10.1016/j.ajpath.2018.01.006},
  volume       = {188},
  year         = {2018},
}