Role of Epithelial Cells in Initiation and Propagation of Intestinal Inflammation. Eliminating the Static: Tight Junction Dynamics Exposed Regulators of the Actin Cytoskeleton Modify Epithelial Barrier Function
Role of Epithelial Cells in Initiation and Propagation of Intestinal Inflammation. Eliminating the Static: Tight Junction Dynamics Exposed Regulators of the Actin Cytoskeleton Modify Epithelial Barrier Function
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Le Shen;J. Turner;Shen;Jerrold R Turner Le
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作者：
Le Shen;J. Turner;Shen;Jerrold R Turner Le
表面，肠形成了一个屏障，将外部环境，即，肠腔，从保护内部环境。肠屏障由排列在管腔表面的上皮细胞形成。这些细胞的质膜阻止亲水性分子自由通过该屏障，但不密封细胞之间的空间。该功能由紧密连接提供。每个细胞在顶外侧边界处被紧密连接包围，紧密连接密封细胞旁空间。然而，紧密连接并不形成完全不渗透的密封，因为这会阻止必需营养素和离子的细胞旁吸收;肠紧密连接是“泄漏的“，并允许溶质根据大小和电荷进行细胞旁转运。大量的数据表明，可以调制的生理，药理学和病理生理刺激的紧密连接的屏障特性，但负责这些反应的结构修饰定义不清。最近的进展，在理解的作用，紧密连接动力学在响应这些刺激是本次审查的重点。紧密连接屏障不是静态的，而是可以受到多种外部因素的调节。例如，生理刺激，如Na +-葡萄糖共转运的启动，可引起紧密连接通透性的快速和可逆增加（22）。这种调节的特征在于渗透性的小幅增加，这被认为是对营养物质的细胞旁转运进行微调;对小分子的渗透性增加，而不增加较大分子的通过。形态学和机制研究均表明，Na +-葡萄糖共转运启动后的紧密连接调节取决于肌动蛋白细胞骨架的调节，而肌动蛋白细胞骨架与紧密连接密切相关（12）。与肌动蛋白细胞骨架在紧密连接功能中的重要作用一致，长期以来人们一直知道肌动蛋白的药理学破坏，例如肌动蛋白解聚药物诱导的破坏，会导致广泛的紧密连接破坏（2）。与Na +-葡萄糖共转运触发的调节相反，肌动蛋白解聚的作用是剧烈的，导致屏障功能的显著丧失。因此，这代表了生理和病理生理反应的夸张形式，使其成为紧密连接调节机制研究的有用模型。许多病理生理效应物，包括促炎性细胞因子和非侵入性细菌，似乎也通过肌动蛋白细胞骨架改变上皮紧密连接屏障功能（24，25）。一般来说，这些渗透率增加的幅度相对于…
surfaces, the intestine forms a barrier that separates the external environment, i.e., the gut lumen, from the protected internal milieu. The intestinal barrier is formed by the epithelial cells that line the luminal surface. Plasma membranes of these cells prevent free passage of hydrophilic molecules across this barrier but do not seal the space between cells. This function is provided by the tight junction. Each cell is encircled at the apicolateral boundary by the tight junction, which seals the paracellular space. The tight junction does not form a completely impermeant seal, however, because that would prevent paracellular absorption of essential nutrients and ions; intestinal tight junctions are " leaky " and allow solutes to be transported paracellularly according to size and charge. Abundant data are available to demonstrate that barrier properties of tight junctions can be modulated in response to physiological, pharmacological, and patho-physiological stimuli, but the structural modifications responsible for these responses are poorly defined. Recent advances in understanding the role of tight junction dynamics in response to such stimuli are the focus of this review. The tight junction barrier is not static, but can be regulated by multiple external factors. For example, physiological stimuli , such as initiation of Na ϩ-glucose cotransport, can effect rapid and reversible increases in tight junction permeability (22). This regulation is characterized by small increases in permeability that are thought to fine-tune paracellular transport of nutrients; permeability to small molecules is increased without increased passage of larger molecules. Both morphological and mechanistic studies have suggested that tight junction regulation following initiation of Na ϩ-glucose cotransport depends on modulation of the actin cytoskeleton, which is intimately associated with the tight junction (12). Consistent with an essential role for the actin cytoskeleton in tight junction function, it has long been known that pharmacological disruption of actin, such as that induced by actin-depolymerizing drugs, causes extensive tight junction disruption (2). In contrast to regulation triggered by Na ϩ-glucose cotransport, the effects of actin depolymerization are drastic, resulting in marked loss of barrier function. Thus this represents an exaggerated form of physiological and pathophysiological responses, making it a useful model for mechanistic studies of tight junction regulation. Many pathophysiological effectors, including proinflam-matory cytokines and noninvasive bacteria, also appear to modify epithelial tight junction barrier function via the actin cytoskeleton (24, 25). In general, the magnitude of these permeability increases is intermediate relative to the small changes that …