Mechanisms of increased endothelial permeability
Mechanisms of increased endothelial permeability
复制标题
DOI：
10.1139/cjpp-74-7-787
复制
发表时间：
1996-07-01
影响因子：
2.1
通讯作者：
Malik, AB
中科院分区：
文献类型：
--
作者：
Lum, H;Malik, AB
响应于炎性介质如凝血酶和组胺的内皮渗透性的增加伴随着可逆的细胞变圆和内皮间隙形成，表明主要的转运途径是扩散途径（即，通过细胞连接（细胞旁转运））。然而，囊泡介导的转运（即，通过白蛋白结合蛋白GP 60）也可以显著地促进渗透性的总体增加。内皮细胞中细胞旁转运的调节与基于肌动蛋白的系统的调节相关，肌动蛋白系统将细胞锚到其邻近细胞或细胞外基质，从而维持内皮完整性。在细胞-细胞连接处，肌动蛋白通过连接蛋白质（例如，黏着斑蛋白、连环蛋白、α-辅肌动蛋白）到钙粘蛋白，其在嗜同性细胞间粘附中起作用。在内皮局灶接触处，基质蛋白的跨膜受体（整联蛋白）通过连接蛋白（即，黏着斑蛋白、talin、α-辅肌动蛋白）。在炎症介质的反应中，第二信使信号的两个调节途径，其调节肌动蛋白为基础的系统，并因此可以导致内皮屏障完整性的损害。一个关键信号可能是基于蛋白激酶C同工酶特异性磷酸化的连接蛋白在细胞-细胞和细胞-基质连接。增加的磷酸化与肌动蛋白重组、细胞变圆和增加的细胞旁转运有关。另一个重要事件是肌球蛋白轻链激酶（MLCK）的激活，其引起基于肌动蛋白-肌球蛋白的收缩，这可能导致内皮细胞的向心收缩。目前的研究正在进行蛋白激酶C同工酶的蛋白底物的鉴定，其磷酸化在屏障功能中的具体作用，以及MLCK在调节内皮屏障功能中的确切作用的测定。由于增加的渗透性恢复正常的机制可以在多个水平上调节（例如，受体脱敏、蛋白激酶C介导的负反馈途径、蛋白磷酸酶的激活），确定这些细胞“关闭”机制也很重要。
The increase in endothelial permeability in response to inflammatory mediators such as thrombin and histamine is accompanied by reversible cell rounding and interendothelial gap formation, suggesting that the predominant transport pathway is a diffusive one (i.e., via cellular junctions (paracellular transport)). However, vesicle-mediated transport (i.e., via albumin-binding protein gp60) may also contribute significantly to the overall increase in permeability. Regulation of paracellular transport in endothelial cells is associated with modulation of actin-based systems, which anchor the cell to its neighbor or extracellular matrix, thus maintaining endothelial integrity. At the cell-cell junctions, actin is linked indirectly to the plasma membrane by linking proteins (e.g., vinculin, catenins, alpha-actinin) to cadherins, which function in homophilic intercellular adhesion. At endothelial focal contacts, the transmembrane receptors (integrins) for matrix proteins are linked to actin via linking proteins (i.e., vinculin, talin, a-actinin). In response to inflammatory mediators, second messengers signal two regulatory pathways, which modulate the actin-based systems, and can thus lead to impairment of the endothelial barrier integrity. One critical signal may be based on protein kinase C isoenzyme specific phosphorylation of linking proteins at the cell-cell and cell-matrix junctions. The increased phosphorylation is associated with actin reorganization, cell rounding, and increased paracellular transport. Another important event is the activation of myosin light chain kinase (MLCK), which causes an actin-myosin-based contraction that may lead to centripetal retraction of endothelial cells. Current research is being conducted at identification of protein substrates of protein kinase C isoenzymes, the specific role of their phosphorylation in barrier function, and determination of the precise role of MLCK in modulation of endothelial barrier function. Since mechanisms by which the increased permeability is returned to normal may be regulated at multiple levels (e.g., receptor desensitization, protein kinase C mediated negative feedback pathways, activation of protein phosphatases), it is also important to determine these cellular "off-switch" mechanisms.