Article Text

Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention
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  1. Melanie Königshoff1,
  2. Rio Dumitrascu2,
  3. Sergey Udalov2,
  4. Oana Veronica Amarie1,
  5. Rudolf Reiter3,
  6. Friedrich Grimminger2,
  7. Werner Seeger2,
  8. Ralph Theo Schermuly2,4,
  9. Oliver Eickelberg1
  1. 1Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University Munich, Asklepios Hospital Gauting, and Helmholtz Zentrum München, Munich, Germany
  2. 2Department of Medicine, University of Giessen Lung Center, Giessen, Germany
  3. 3Ergonex Pharma GmbH, Appenzell, Switzerland
  4. 4Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
  1. Correspondence to Oliver Eickelberg, Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University Munich and Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg/München, Germany; oliver.eickelberg{at}helmholtz-muenchen.de

Abstract

Background Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro.

Methods and results Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride (or vehicle) in a therapeutic approach (days 14–28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β1- or WNT3a-induced collagen production.

Conclusion The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

  • Serotonin
  • collagen
  • tissue remodelling
  • Interstitial fibrosis

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Supplementary materials

  • Web Only Data THORAX.2010.134353

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Footnotes

  • Funding The authors are supported by the Helmholtz Association, the German Research Foundation (DFG) KliFo 118 and a career development award by the University of Giessen School of Medicine to MK.

  • Competing interests RR is a full-time employee of Ergonex Pharma.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the University of Giessen.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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