期刊
EUROPEAN RESPIRATORY JOURNAL
卷 37, 期 5, 页码 1104-1118出版社
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/09031936.00126010
关键词
Collagen; experimental therapeutics; inflammation; pulmonary hypertension; smooth muscle cells; vascular remodelling
资金
- Ergonex
- Deutsche Forschungsgemeinschaft [SFB547]
- European Commission [LSHM-CT-2005-018725]
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a preclinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR2A/B on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR2B upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.
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