Protective Role of Rho Guanosine Diphosphate Dissociation Inhibitor, Ly-GDI, in Pulmonary Alveolitis.
Protective Role of Rho Guanosine Diphosphate Dissociation Inhibitor, Ly-GDI, in Pulmonary Alveolitis.
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Rho 鸟苷二磷酸解离抑制剂 Ly-GDI 在肺泡炎中的保护作用
DOI：
10.1371/journal.pone.0140804
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Yan C;Wang X;Liu Y;Abdulnour RE;Wu M;Gao H
越来越多的证据表明，Rho GTP酶的抑制蛋白Ly-GDI在调节肌动蛋白细胞骨架变化中起着重要作用，而细胞骨架变化是吞噬等过程中不可或缺的。然而，Ly-GDI在炎症中的作用在很大程度上仍不清楚。在目前的研究中，我们发现在免疫复合物损伤的肺组织中，Ly-GDI的表达显著降低。为了确定Ly-GDI是否可以调节肺部炎症反应，我们构建了能够介导Ly-GDI异位表达的腺病毒载体(Adeno-Ly-GDI)。在小鼠肺内表达Ly-GDI可明显减轻免疫复合物所致的肺损伤，其机制可能与肺通透性降低，肺炎性细胞尤其是中性粒细胞聚集有关。在免疫复合物沉积方面，与对照组相比，肺内高表达Ly-GDI的小鼠在支气管肺泡灌洗液中产生的炎症介质(肿瘤坏死因子-α、IL-6、单核细胞趋化蛋白-1和巨噬细胞趋化蛋白-1α)明显减少。荧光素酶分析和凝胶迁移率改变分析表明，Ly-κ可显著抑制免疫复合物诱导的肺泡巨噬细胞和肺组织中的NF-GDIB活性。提示Ly-GDi是免疫复合物沉积后炎性损伤的重要调节因子，对肺组织中的NF-κB活性具有负性调节作用。
Growing evidences indicate that Ly-GDI, an inhibitory protein of Rho GTPases, plays an essential role in regulating actin cytoskeletal alteration which is indispensible for the process such as phagocytosis. However, the role of Ly-GDI in inflammation remains largely unknown. In the current study, we found that Ly-GDI expression was significantly decreased in the IgG immune complex-injured lungs. To determine if Ly-GDI might regulate the lung inflammatory response, we constructed adenovirus vectors that could mediate ectopic expression of Ly-GDI (Adeno-Ly-GDI). In vivo mouse lung expression of Ly-GDI resulted in a significant attenuation of IgG immune complex-induced lung injury, which was due to the decreased pulmonary permeability and lung inflammatory cells, especially neutrophil accumulation. Upon IgG immune complex deposition, mice with Ly-GDI over-expression in the lungs produced significant less inflammatory mediators (TNF-α, IL-6, MCP-1, and MIP-1α) in bronchoalveolar lavage fluid when compared control mice receiving airway injection of Adeno-GFP. Mechanically, IgG immune complex-induced NF-κB activity was markedly suppressed by Ly-GDI in both alveolar macrophages and lungs as measured by luciferase assay and electrophoretic mobility shift assay. These findings suggest that Ly-GDI is a critical regulator of inflammatory injury after deposition of IgG immune complexes and that it negatively regulates the lung NF-κB activity.