Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

作者：Hélène Le Ribeuz, Lucie To, Maria‐Rosa Ghigna, Clémence Martin, Chandran Nagaraj, Elise Dréano, Catherine Rücker‐Martin, Barbara Girerd, Jérôme Bouligand, Christine Péchoux, Mélanie Lambert, Angèle Boët, Justin Issard, Olaf Mercier, Konrad Höetzenecker, Boris Manoury, Frédéric Becq, Pierre‐Régis Burgel, Charles‐Henry Cottart, Andrea Olschewski, Isabelle Sermet‐Gaudelus, Frédéric Perros, Marc Humbert, David Montani, Fabrice Antigny · 发表于：European Respiratory Journal · 年份：2021 · DOI：10.1183/13993003.00653-2020 · 被引用次数：34 · 研究领域：Cystic Fibrosis Research Advances、Pulmonary Hypertension Research and Treatments、Asthma and respiratory diseases

Introduction A reduction in pulmonary artery relaxation is a key event in the pathogenesis of pulmonary arterial hypertension (PAH). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in airway epithelial cells plays a central role in cystic fibrosis; CFTR is also expressed in pulmonary arteries and has been shown to control endothelium-independent relaxation. Aim and objectives We aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models. Methods and results Reverse-transcriptase quantitative PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in pulmonary arteries from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myography on human, pig and rat pulmonary arteries, we demonstrated that CFTR activation induces pulmonary artery relaxation. CFTR-mediated pulmonary artery relaxation was reduced in pulmonary arteries from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-termin vivoCFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferationin situand vessel neomuscularisation. Pathologic assessment of lungs from patients with severe cystic fibrosis (F508del-CFTR) revealed severe pulmonary artery remodelling with intimal fibrosis and medial hypert...