连接蛋白40在急性肺损伤中的作用及机制

Previously, we found local pro-inflammatory stimuli evoke Ca2+ response and inflammatory response via TPRV4 channel in lung endothelial cells, our further study shows that this pro-inflammatory Ca2+ signal is transmitted to neighbouring cells via connexin 40 (Cx40) and decays rapidly, which leads to less exocytosis of P-selectin, attenuation of lung inflammation and subdued acute lung injury (ALI). Inhibition or genetical elimination of Cx40 both cause in situ accumulation of Ca2+, as well as enhanced P-seletin exocytosis, neutrophil adhesion, lung inflammation and ALI. Cx40, distributed closely with TRPV4 and eNOS, has a significant reduction of its expression in ALI. While using bone marrow stromal cells (BMSCs) to treat ALI, we noticed a strong correlation of Cx40 expression and BMSCs adhesion in lung vessels. Considering the in vitro findings that Cxs mediate mitochondria transfer and help to restore cell energy metabolism, combining in vivo, ex vivo and in vitro models, we aim to test our hypothesis that Cx40 mediates Ca2+ propagation/decay and P-seletin expression/neutrophil adhesion, regulates NO production and controls the therapeutic effects of BMSCs for ALI, our study may provide novel method and evidence for the therapy of ALI

前期我们发现局部炎症刺激激活TRPV4通道引起Ca2+信号及炎症反应，现进一步发现此Ca2+信号通过连接蛋白40(Cx40)向相邻内皮细胞迅速弥散而衰减，减少了P选择素表达，阻断或基因敲除Cx40均导致TRPV4介导的Ca2+信号在炎症刺激局部集聚，增强了P选择素的表达及中性粒细胞(PMN)的粘附，以及肺组织炎症反应和肺损伤(ALI)。Cx40不仅在ALI时表达下降，而且与TRPV4和eNOS共同分布。在运用骨髓基质细胞(BMSCs)治疗ALI的实验中，我们发现Cx40表达与BMSCs在肺血管中粘附呈相关性。结合体外实验中Cx能介导线粒体转移的发现，本研究旨在从机体整体功能、肺局部功能及分子生物学角度，对Cx40在ALI中的作用及机制进行研究，以验证我们关于Cx40调节Ca2+弥散及P选择素表达、PMN粘附，调控NO生成和BMSCs治疗ALI作用的设想，从而为治疗ALI提供新的方法和依据。

前期我们发现局部炎症刺激激活TRPV4通道引起Ca2+信号及炎症反应，现进一步发现此Ca2+信号通过连接蛋白40(Cx40)向相邻内皮细胞迅速弥散而衰减，减少了P选择素表达，阻断或基因敲除Cx40均导致TRPV4介导的Ca2+信号在炎症刺激局部集聚，增强了P选择素的表达及中性粒细胞(PMN)的粘附，以及肺组织炎症反应和肺损伤(ALI)。Cx40不仅在ALI时表达下降，而且与TRPV4和eNOS共同分布。在运用骨髓基质细胞(BMSCs)治疗ALI的实验中，我们发现Cx40表达与BMSCs在肺血管中粘附呈相关性。结合体外实验中Cx能介导线粒体转移的发现，本研究旨在从机体整体功能、肺局部功能及分子生物学角度，对Cx40在ALI中的作用及机制进行研究，以验证我们关于Cx40调节Ca2+弥散及P选择素表达、PMN粘附，调控NO生成和BMSCs治疗ALI作用的设想，从而为治疗ALI提供新的方法和依据。