PDF(Pubmed)
Abstract：
Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. We recently reported that endothelial cell (EC) TRPV4 channels play a central role in lung edema and dysfunction after IR. However, the cellular mechanisms for lung IR-induced activation of endothelial TRPV4 channels are unknown. In a left-lung hilar ligation model of IRI in mice, we found that lung IR increases the efflux of extracellular ATP (eATP) through pannexin 1 (Panx1) channels at the EC membrane. Elevated eATP activated elementary Ca2+ influx signals through endothelial TRPV4 channels through purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro surrogate models of lung IR. Endothelium-specific deletion of P2Y2R, TRPV4, and Panx1 in mice had substantial protective effects against lung IR-induced activation of endothelial TRPV4 channels, lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a novel mediator of lung edema, inflammation, and dysfunction after IR, and show that disruption of endothelial Panx1-P2Y2R-TRPV4 signaling pathway could represent a promising therapeutic strategy for preventing lung IRI after transplantation.
摘要：
肺缺血再灌注损伤(IRI),以炎症为特征，血管通透性,和肺水肿，是肺移植后原发性移植物功能障碍的主要原因。我们最近报道，内皮细胞（EC）TRPV4通道在IR后肺水肿和功能障碍中起重要作用。然而,肺IR诱导的内皮TRPV4通道激活的细胞机制尚不清楚.在小鼠IRI的左肺门结扎模型中，我们发现肺IR增加了细胞外ATP（eATP）通过EC膜上的pannexin1（Panx1）通道的流出。eATP通过嘌呤能P2Y2受体（P2Y2R）信号通过内皮TRPV4通道激活基本Ca2内流信号。在离体和体外肺IR替代模型中，在人和小鼠肺微血管内皮中也观察到了TRPV4通道的P2Y2R依赖性激活。P2Y2R的内皮特异性缺失,小鼠中的TRPV4和Panx1对肺IR诱导的内皮TRPV4通道激活具有实质性的保护作用，肺水肿,炎症,和功能障碍。这些结果确定内皮P2Y2R是肺水肿的新介质，炎症,和IR后的功能障碍，并显示内皮细胞Panx1-P2Y2R-TRPV4信号通路的破坏可能代表一种有希望的预防移植后肺IRI的治疗策略。
