American Journal of Pathology
American Journal of Pathology
5 years ago

Effects of 5-HT2 receptor antagonists on bronchoconstriction and pulmonary remodeling processes

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-HT2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pre-treated with 5-HT2B receptor antagonists; EXT5, EXT9, RS127445, and PRX08066, as well as ketanserin (5-HT2A/2C receptor antagonist) (1 μM, 10 μM), prior to addition of cumulative concentrations of 5-HT to induce bronchoconstriction. Remodeling effects following treatment with 10 μM 5-HT and 5-HT2 receptor antagonists were further studied in distal lung tissue—examining release of pro-fibrotic transforming growth factor (TGF)-β1; as well as proliferation of human bronchial smooth muscle cells (HBSMC). 5-HT–induced bronchoconstriction was significantly reduced by EXT5, EXT9, and ketanserin, but not by RS127445 or PRX08066. The 5-HT2B receptor antagonists significantly reduced TGF-β1 release. 5-HT, in combination with TGF-β1, increased proliferation of HBSMC, a process reduced by EXT5, 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 anti-proliferative effect on HBSMC and the inhibition of TGF-β1 release further supports a role of 5-HT2B receptors in pathological remodeling processes.

Publisher URL: www.sciencedirect.com/science

DOI: S0002944017308982

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