Role of P2X7R in the development and progression of pulmonary hypertension

作者：Jie Yin, Shuling You, Haopeng Liu, Li Chen, Chengdong Zhang, Hesheng Hu, Mei Xue, Wenjuan Cheng, Ye Wang, Xinran Li, Xinran Li, Yugen Shi, Nannan Li, Suhua Yan, Xiaolu Li, Xiaolu Li · 发表于：Respiratory Research · 年份：2017 · DOI：10.1186/s12931-017-0603-0 · 被引用次数：45 · 研究领域：Pulmonary Hypertension Research and Treatments、Obstructive Sleep Apnea Research、Adenosine and Purinergic Signaling

Pulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X 7 receptor (P2X 7 R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH. PH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness. Marked P2X 7 R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X 7 R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X 7 receptor antagonist, 30 mg/kg) daily starting from 1 week before or 2 weeks after MCT injection. Consequently, A-740003 reversed the NLRP3 inflammasome upregulation, significantly decreased the mean right ventricular (RV) pressure and RV hypertrophy, and reversed pulmonary arterial remodelling 4 weeks after MCT injection, as both a pretreatment and rescue intervention. Notably, A-740003 significantly reduced macrophage and pro-inflammatory cytokine levels, as measured via bronchoalveolar lavage. The recruitment of macrophages as well as collagen fibre deposition in the perivascular areas were...