Early growth response factor-1 in acute lung injury
Early growth response factor-1 in acute lung injury
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DOI：
10.1152/ajplung.00265.2007
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发表时间：
2007-11-01
影响因子：
4.9
通讯作者：
Kavanagh, Brian P.
中科院分区：
文献类型：
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作者：
Ngiam, Nicola;Post, Martin;Kavanagh, Brian P.
早期生长反应因子-1 (EGR1) 是一种核转录因子，于 15 年前被发现，属于一个更大的早期反应基因家族。它似乎是许多信号传导途径的汇聚点，包括那些涉及炎症和细胞凋亡的信号传导途径，并且其表达会被各种刺激迅速诱导。诱导的 EGR1 蛋白被认为通过改变 EGR1 靶基因（例如组织因子、血管内皮生长因子 (VEGF)、细胞间粘附分子 1 (ICAM1) 以及器官损伤中常见的蛋白质）的表达，将外部刺激与细胞内事件耦合起来。由于 EGR1 似乎介导对脓毒症 (22) 和再灌注损伤 (28) 的反应，并增强炎症反应 (28)，因此它可能在危重疾病的发病机制中发挥重要作用。这一观点旨在总结目前对 EGR1 在急性疾病状态中的作用和机制的了解。 EGR1 和急性肺损伤。 EGR1 由肺部的多种刺激诱导，包括缺氧 (29)、高氧、缺血再灌注 (28) 和高潮气量 (4)。暴露于低氧浓度 (6–20%) 会导致 EGR1 mRNA 诱导，随着氧气浓度较低和暴露时间较长，EGR1 mRNA 诱导程度会更大 (29)。继发于缺氧的 EGR1 DNA 结合上调也被证明可以激活单核巨噬细胞中的组织因子，并且其缺失（即在 EGR1 缺失小鼠中）与暴露于缺氧后组织因子激活和肺部纤维蛋白沉积减少相关 (30)。最近的一项研究支持了这些发现，其中 EGR1 蛋白上调极大地增强了暴露于缺氧后小鼠巨噬细胞中丝氨酸蛋白酶抑制剂肽酶抑制剂、进化枝 E（nexin，纤溶酶原激活剂抑制剂 1 型）成员 1 (SERPINE1) 的诱导 (17)。这可能尤其重要，因为 SERPINE1 在抑制纤维蛋白溶解方面发挥着关键作用，因此其上调可能是缺氧诱导血栓形成的必要因素 (17)。缺血再灌注反映了许多急性疾病状态的核心过程。在小鼠肺缺血再灌注中，EGR1 mRNA 上调很明显，并且局限于肺巨噬细胞和平滑肌细胞 (28)。此外，与野生型小鼠相比，EGR1 敲除小鼠在肺缺血再灌注后存活时间更长，循环炎症介质水平更低，纤维蛋白和白细胞积累减少 (28)。在敲除小鼠中，LPS（即内毒素）给药（脓毒症模型）强烈激活了上述缺血再灌注模型中检查的相同炎症介质。这项研究表明 EGR1 激活参与了缺血性肺组织损伤的发病机制，并描述了所涉及的特定下游炎症介质，包括 ICAM1、IL-1、凝血因子 III（凝血活酶、组织因子）(F3)、SERPINE1 和 VEGF (28)。我们之前使用基因阵列技术发现，大鼠的高潮气量通气增加了多个基因的表达，包括 EGR1 (4)。这种上调在有害通气开始后 30 分钟且早在组织学评估可证实肺损伤之前就很明显 (4)。这些发现在体外拉伸的胎儿肺上皮细胞中得到了进一步证实 (5)。
EARLY GROWTH RESPONSE FACTOR-1 (EGR1), a nuclear transcription factor, was discovered 15 years ago and belongs to a larger family of early response genes. It appears to function as a convergence point for many signaling pathways, including those involved in inflammation and apoptosis, and its expression is rapidly induced by a variety of stimuli. The induced EGR1 protein is thought to couple external stimuli to intracellular events by altering the expression of EGR1 target genes such as tissue factor, vascular endothelial growth factor (VEGF), intercellular adhesion molecule 1 (ICAM1), proteins that are common in organ injury. Because EGR1 appears to mediate responses to sepsis (22) and reperfusion injury (28), as well as intensify inflammatory responses (28), it may be important in the pathogenesis of critical illness. This perspective aims to summarize the current state of knowledge of the effects and mechanisms of EGR1 in acute illness states. EGR1 and acute lung injury. EGR1 is induced by a variety of stimuli in the lung, including hypoxia (29), hyperoxia, ischemia-reperfusion (28), and high tidal volume (4). Exposure to low oxygen concentrations (6–20%) resulted in EGR1 mRNA induction that was greater with lower O2 concentrations and longer exposure times (29). Upregulation of EGR1 DNA binding secondary to hypoxia was also shown to activate tissue factor in mononuclear macrophages, and its absence (ie, in EGR1 null mice) was associated with reduced tissue factor activation and fibrin deposition in the lungs following exposure to hypoxia (30). Supporting these findings is a recent study in which EGR1 protein upregulation greatly augmented the induction of serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1 (SERPINE1) in mouse macrophages following exposure to hypoxia (17). This may be especially important as SERPINE1 plays a key role in suppressing fibrinolysis, and its upregulation could therefore be a necessary element in the development of hypoxia-induced thrombosis (17). Ischemia-reperfusion reflects processes that are central to many acute illness states. In murine pulmonary ischemiareperfusion, EGR1 mRNA upregulation was evident and localized to lung macrophages and smooth muscle cells (28). Moreover, EGR1 knockout mice had longer survival and lower levels of circulating inflammatory mediators, as well as reduced fibrin and leukocyte accumulation compared with wild-type mice, following exposure to pulmonary ischemiareperfusion (28). The same inflammatory mediators examined in the ischemia-reperfusion model stated above were strongly activated by LPS (ie, endotoxin) administration, a model of sepsis, in the knockout mice. This study implicates EGR1 activation in the pathogenesis of ischemic lung tissue damage and delineates specific downstream inflammatory mediators involved, including ICAM1, IL-1, coagulation factor III (thromboplastin, tissue factor)(F3), SERPINE1, and VEGF (28).We have previously found, using gene array techniques, that high tidal volume ventilation in rats increased the expression of several genes, including EGR1 (4). This upregulation was evident 30 min after the initiation of injurious ventilation and well before lung injury was demonstrable by histological assessment (4). These findings were further substantiated in fetal lung epithelial cells subjected to in vitro stretch (5).