前B细胞克隆增强因子在体外循环术后肺血管内皮通透性增加中的机制研究

Postoperative lung injury is one of the most frequent complications of cardiac surgery.Increased pulmonary vascular endothelial permeability is the main reason.Our and other studies found that the expression of pre-B-cell colony enhancing factor significantly increased in pulmonary vascular endothelial cells induced by acute lung injury.Reductions in PBEF protein expression significantly attenuated endothelial cell barrier dysfunction.Our another study had proved that the mitogen-activated protein kinases (MAPKs) was an important signaling pathway in the mechanism of acute lung injury after cardiopulmonary bypass.However, either one of MAPKs or some of them plays a key role in regulating pulmanory vascular endothelial permeability,and how does the cytoskeletal structural components change remain to be elucidated.In this study,we intend to use the hypoxia/reoxygenation(H/R) model of pulmonary vascular endothelial cells(PVECS) and the Deep Hypothermic Circulatory Arrest(DHCA) model of rats to clarify it.Furthermore, based on the cell and animal models, we would like to investigate the protein expression of MAPKs and changing of pulmonary vascular endothelial cytoskeletal structural components induced by the overexpression and low expression of PBEF protein.According to the results of our study,we will find the mechanism of increased pulmonary vascular endothelial permeability induced by pre-B-cell colony enhancing factor after cardiopulmonary bypass and provide a new insight in preventing pulmonary dysfunction after cardiopulmonary bypass.

肺血管内皮通透性增加是体外循环（CPB）术后肺损伤的一个重要的原因。我们的研究和已有报道显示，急性肺损伤肺血管内皮通透性增加时前B细胞克隆增强因子（PBEF）的表达明显增加，下调PBEF表达能明显改善肺血管通透性。我们之前和他人的研究还证实MAPK家族信号通路是调控CPB术后肺损伤的重要通路，并且在PBEF引起的细胞通透性改变方面其重要作用。MAPK家族的哪一个或者哪些通路参与了PBEF调控肺血管内皮通透性增加及PBEF引起肺血管内皮骨架结构改变的靶点目前尚不清楚。本项目拟用基因转染、RNAi和PBEFshRNA慢病毒载体技术采用肺血管内皮细胞缺氧复氧模型和大鼠深低温停循环模型在细胞和动物水平研究，观察PBEF低表达、高表达时MAPK家族表达变化情况及肺血管内皮构象改变靶点。阐明PBEF调控肺血管内皮通透性增加的信号机制和作用靶点，为临床心脏外科CPB术后肺损伤和肺保护提供一个新的理论依据

体外循环（cardiopulmonary bypass,CPB）是心内直视手术必备条件，肺功能障碍是 CPB 术后重要的并发症和高死亡原因之一，肺血管内皮通透性增加是CPB术后肺损伤的一个重要的原因。而体外循环术后急性肺损伤时肺血管内皮通透性增加，前B 细胞克隆增强因子（PBEF）的表达明显增加，下调PBEF 表达能明显改善肺血管通透性。本研究采用HUVECs缺氧／复氧损伤模型和大鼠深低温停循环模型，从细胞及动物模型模拟体外循环术后肺缺血再灌注损伤，检测PBEF与细胞通透性及P38MAPK/ ERK信号通路的调控的关系，结果发现：在细胞和动物水平，PBEF通过P38MAPK/ ERK信号通路影响细胞骨架重排、细胞-细胞间粘附、细胞-基质间粘附，导致肺血管内皮细胞构象改变，产生肺损伤，这些研究结果提示：PBEF 通过P38MAPK / ERK 通路参与了体外循环术后肺血管内皮细胞通透性增加的调节。