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

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-HT_2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT_2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pretreated with 5-HT_2B receptor antagonists (EXT5, EXT9, RS 127445, and PRX 08066), as well as ketanserin (5-HT_2A/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-HT_2B 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_2B receptors in pathologic remodeling processes.