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


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.


CONCLUSIONS
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.
Königshoff
Melanie
M
Comprehensive Pneumology Center, University Hospital of Ludwig Maximilians University Munich, Asklepios Hospital Gauting, and Helmholtz Zentrum München, Munich, Germany.
Dumitrascu
Rio
R
Udalov
Sergey
S
Amarie
Oana Veronica
OV
Reiter
Rudolf
R
Grimminger
Friedrich
F
Seeger
Werner
W
Schermuly
Ralph Theo
RT
Eickelberg
Oliver
O
D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D008090:Lisuride / Q000031:analogs & derivatives / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; C493230:SLC6A4 protein, human; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D001761:Bleomycin; C006208:dironyl; D008090:Lisuride