Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention.

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-HTR(2A) and 5-HTR(2B) 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-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro.

METHODS AND RESULTS:

Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) 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-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/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 β(1)- or WNT3a-induced collagen production.

CONCLUSION:

The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

• Authors: Melanie Königshoff, Rio Dumitrascu, Sergey Udalov, Oana Veronica Amarie, Rudolf Reiter, Friedrich Grimminger, Werner Seeger, Ralph Theo Schermuly, Oliver Eickelberg
• Journal: Thorax (Thorax) Vol. 65 Issue 11 Pg. 949-55 (Nov 2010) ISSN: 1468-3296 [Electronic] England
• PMID: 20671305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Serotonin, 5-HT2A
• Receptor, Serotonin, 5-HT2B
• SLC6A4 protein, human
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Plasma Membrane Transport Proteins
• Bleomycin
• dironyl
• Lisuride

Topics

• Animals
• Bleomycin
• Disease Models, Animal
• Drug Evaluation, Preclinical (methods)
• Female
• Humans
• Lisuride (analogs & derivatives, therapeutic use)
• Lung (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Pulmonary Fibrosis (chemically induced, drug therapy, metabolism)
• Receptor, Serotonin, 5-HT2A (metabolism)
• Receptor, Serotonin, 5-HT2B (metabolism)
• Serotonin 5-HT2 Receptor Antagonists (therapeutic use)
• Serotonin Plasma Membrane Transport Proteins (metabolism)