Role of P2X7R in the development and progression of pulmonary hypertension

Abstract

BackgroundPulmonary 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 resultsPH 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.ConclusionsP2X7R 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0603-0) contains supplementary material, which is available to authorized users.

Activation of Nicotinic Acetylcholine α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome

“…et al, 2018; Wang H. et al, 2018). Previous reports revealed NLRP3 inflammasome as a key factor in the signaling pathway mediating the inflammatory and remodeling effects in the context of PH (Tang et al, 2015; Yin et al, 2017). The activation of the NLRP3 inflammasome occurred after cell stress through the Toll-like receptor 4-ligand interaction and high extracellular ATP levels (Gaikwad et al, 2017).…”

“…Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, comprising the NLRP3, the apoptosis speck-like protein containing a caspase-recruitment domain (ASC), and pro-caspase-1, mediate cytokine and inflammatory responses in PH (Tang et al, 2015; Yin et al, 2017). The NLRP3 inflammasome is predominantly expressed in macrophages and functions as a multiple cytoplasmic sensor molecule (Mangan et al, 2018).…”

Emerging Role of the Inflammasome and Pyroptosis in Hypertension

“…Moreover, absence of the ASC adaptor protein attenuates hypoxia-induced pulmonary hypertension in mice [ 116 ]. Pre-clinical and clinical studies further support the involvement of the NLRP3 inflammasome in pulmonary hypertension [ 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ] and confirm the occurrence of pyroptosis in rat pulmonary arteries and hypoxic human pulmonary smooth muscle cells [ 125 ]. Although more research is clearly needed to better define the exact mechanisms mediated by the NLRP3 inflammasome in leading to pulmonary hypertension, the current evidence surely hints to this pathway as a presumed therapeutic target in this devastating disease.…”

SOD2 ameliorates pulmonary hypertension in a murine model of sleep apnea via suppressing expression of NLRP3 in CD11b+ cells

“…In particular, the NLRP3 pathway leads to inflammation and vascular remodeling, thus contributing to the development of PH [30]. Interestingly, mice lacking NLRP3 display attenuated pulmonary hypertension and a blunted inflammasome activation with decreased caspase-1, IL-18, and IL-1β levels in response to hypoxia induced pulmonary vasoconstriction [31,32]. The mature IL-1β is a prototypic multifunctional cytokine that is involved in pulmonary inflammation and could stimulate chemokines and adhesion molecules, such as MCP-1 and MIP-1α for macrophage recruitment [33,34], which contributed to CD11b + cells mobilization in feedback.…”