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Respiratory Research
Published in: Respiratory Research 1/2017

Open Access 01-12-2017 | Research

Role of P2X7R in the development and progression of pulmonary hypertension

Authors: Jie Yin, Shuling You, Haopeng Liu, Li Chen, Chengdong Zhang, Hesheng Hu, Mei Xue, Wenjuan Cheng, Ye Wang, Xinran Li, Yugen Shi, Nannan Li, Suhua Yan, Xiaolu Li

Published in: Respiratory Research | Issue 1/2017

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Abstract

Background

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 P2X7 receptor (P2X7R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH.

Methods and results

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 P2X7R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X7R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X7 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 also reduced, as confirmed by histological staining.

Conclusions

P2X7R contributes to the pathogenesis of PH, probably in association with activation of the NLRP3 inflammasome. Blockade of P2X7R might be applied as a novel therapeutic approach for the treatment of PAH.
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Metadata
Title
Role of P2X7R in the development and progression of pulmonary hypertension
Authors
Jie Yin
Shuling You
Haopeng Liu
Li Chen
Chengdong Zhang
Hesheng Hu
Mei Xue
Wenjuan Cheng
Ye Wang
Xinran Li
Yugen Shi
Nannan Li
Suhua Yan
Xiaolu Li
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-017-0603-0

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