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Pulmonary fibrosis in vivo displays increased p21 expression reduced by 5-HT2B receptor antagonists in vitro - A potential pathway affecting proliferation

Löfdahl, Anna LU ; Rydell-Törmänen, Kristina LU ; Larsson-Callerfelt, Anna Karin LU ; Wenglén, Christina LU and Westergren-Thorsson, Gunilla LU (2018) In Scientific Reports 8(1).
Abstract

Serotonin (5-hydroxytryptamine) has repeatedly been associated with the development of fibrotic disorders such as pulmonary fibrosis. By blocking the binding of 5-HT to 5-HT2B receptors with receptor antagonists, several pro-fibrotic mechanisms can be inhibited. Bleomycin-induced pulmonary fibrosis is a model used to evaluate pathological mechanisms and pharmacological interventions. Previously we have shown attenuated fibrosis in systemic bleomycin-treated mice following treatment with two 5-HT2B receptor antagonists (EXT5 and EXT9). Our aim is to further identify cellular effects and signaling pathways associated with the anti-fibrotic effects of EXT5/9. Gene expressions in lung tissues from systemic... (More)

Serotonin (5-hydroxytryptamine) has repeatedly been associated with the development of fibrotic disorders such as pulmonary fibrosis. By blocking the binding of 5-HT to 5-HT2B receptors with receptor antagonists, several pro-fibrotic mechanisms can be inhibited. Bleomycin-induced pulmonary fibrosis is a model used to evaluate pathological mechanisms and pharmacological interventions. Previously we have shown attenuated fibrosis in systemic bleomycin-treated mice following treatment with two 5-HT2B receptor antagonists (EXT5 and EXT9). Our aim is to further identify cellular effects and signaling pathways associated with the anti-fibrotic effects of EXT5/9. Gene expressions in lung tissues from systemic bleomycin-treated mice were examined, revealing significant increased expression of Cdkn1α (a gene coding for p21), particularly in distal regions of the lung. In vitro studies in human lung fibroblasts revealed increased levels of p21 (p = 0.0032) and pAkt (p = 0.12) following treatment with 5-HT (10 μM). The induction of p21 and pAkt appears to be regulated by 5-HT2B receptors, with diminished protein levels following EXT9-treatment (p21 p = 0.0024, pAkt p = 0.15). Additionally, 5-HT induced fibroblast proliferation, an event significantly reduced by EXT5 (10 μM) and EXT9 (10 μM). In conclusion, our results suggest that 5-HT2B receptor antagonism attenuates pulmonary fibrosis in part by anti-proliferative effects, associated with inhibited pAkt/p21 signaling pathway.

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organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
8
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85041631463
ISSN
2045-2322
DOI
10.1038/s41598-018-20430-0
language
English
LU publication?
yes
id
9bb3cf91-6374-41c3-8803-835c7241beeb
date added to LUP
2018-02-20 07:35:31
date last changed
2018-05-29 10:49:52
@article{9bb3cf91-6374-41c3-8803-835c7241beeb,
  abstract     = {<p>Serotonin (5-hydroxytryptamine) has repeatedly been associated with the development of fibrotic disorders such as pulmonary fibrosis. By blocking the binding of 5-HT to 5-HT<sub>2B</sub> receptors with receptor antagonists, several pro-fibrotic mechanisms can be inhibited. Bleomycin-induced pulmonary fibrosis is a model used to evaluate pathological mechanisms and pharmacological interventions. Previously we have shown attenuated fibrosis in systemic bleomycin-treated mice following treatment with two 5-HT<sub>2B</sub> receptor antagonists (EXT5 and EXT9). Our aim is to further identify cellular effects and signaling pathways associated with the anti-fibrotic effects of EXT5/9. Gene expressions in lung tissues from systemic bleomycin-treated mice were examined, revealing significant increased expression of Cdkn1α (a gene coding for p21), particularly in distal regions of the lung. In vitro studies in human lung fibroblasts revealed increased levels of p21 (p = 0.0032) and pAkt (p = 0.12) following treatment with 5-HT (10 μM). The induction of p21 and pAkt appears to be regulated by 5-HT<sub>2B</sub> receptors, with diminished protein levels following EXT9-treatment (p21 p = 0.0024, pAkt p = 0.15). Additionally, 5-HT induced fibroblast proliferation, an event significantly reduced by EXT5 (10 μM) and EXT9 (10 μM). In conclusion, our results suggest that 5-HT<sub>2B</sub> receptor antagonism attenuates pulmonary fibrosis in part by anti-proliferative effects, associated with inhibited pAkt/p21 signaling pathway.</p>},
  articleno    = {1927},
  author       = {Löfdahl, Anna and Rydell-Törmänen, Kristina and Larsson-Callerfelt, Anna Karin and Wenglén, Christina and Westergren-Thorsson, Gunilla},
  issn         = {2045-2322},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Pulmonary fibrosis in vivo displays increased p21 expression reduced by 5-HT<sub>2B</sub> receptor antagonists in vitro - A potential pathway affecting proliferation},
  url          = {http://dx.doi.org/10.1038/s41598-018-20430-0},
  volume       = {8},
  year         = {2018},
}