Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage
Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage
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DOI：
10.1152/ajplung.00479.2006
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发表时间：
2007-05-01
影响因子：
4.9
通讯作者：
Chaudry, Irshad H.
中科院分区：
文献类型：
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作者：
Hsieh, Ya-Ching;Frink, Michael;Chaudry, Irshad H.
虽然研究表明，17 β-雌二醇（E2）防止中性粒细胞浸润和器官损伤后创伤出血，E2抑制中性粒细胞迁移的机制仍然未知。巨噬细胞移动抑制因子（MIF）被认为在炎症的加重中起核心作用，并与肺损伤有关。MIF通过调节Toll样受体4（TLR 4）来调节炎症反应。TLR 4的激活导致促炎细胞因子和趋化因子的释放，其诱导中性粒细胞浸润和随后的组织损伤。我们推测，E2介导其有益的影响，在肺创伤出血后，通过负调节MIF和TLR 4和姜黄素诱导的趋化性的调制。使C3 H/HeOuJ小鼠经受创伤-出血（平均血压35 +/-5mmHg持续类似于90分钟，然后复苏）或假手术。小鼠接受载体、E2或E2与重组小鼠MIF蛋白（rMIF）的组合。创伤出血增加了肺MIF和TLR 4蛋白水平以及肺和全身细胞因子/趋化因子水平。在创伤出血后用E2治疗动物可以防止这些变化。然而，给予rMIF蛋白和E2消除了E2介导的肺TLR 4水平、肺和血浆IL-6、TNF-α、单核细胞趋化蛋白-1和角质形成细胞衍生趋化因子（KC）水平的降低。rMIF蛋白的管理也防止E2介导的减少中性粒细胞流入和组织损伤的肺创伤出血后。这些结果表明，E2对创伤出血后肺损伤的保护作用是通过下调肺MIF和TLR 4诱导的细胞因子/趋化因子的产生介导的。
Although studies have shown that 17 beta-estradiol (E2) prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which E2 inhibits neutrophil transmigration remains unknown. Macrophage migration inhibitory factor (MIF) is thought to play a central role in exacerbation of inflammation and is associated with lung injury. MIF regulates the inflammatory response through modulation of Toll-like receptor 4 (TLR4). Activation of TLR4 results in the release of proinflammatory cytokines and chemokines, which induce neutrophil infiltration and subsequent tissue damage. We hypothesized that E2 mediates its salutary effects in the lung following trauma-hemorrhage via negative regulation of MIF and modulation of TLR4 and cytokine-induced chemotaxis. C3H/HeOuJ mice were subjected to trauma-hemorrhage (mean blood pressure 35 +/- 5 mmHg for similar to 90 min, then resuscitation) or sham operation. Mice received vehicle, E2, or E2 in combination with recombinant mouse MIF protein (rMIF). Trauma-hemorrhage increased lung MIF and TLR4 protein levels as well as lung and systemic levels of cytokines/chemokines. Treatment of animals with E2 following trauma-hemorrhage prevented these changes. However, administration of rMIF protein with E2 abolished the E2-mediated decrease in lung TLR4 levels, lung and plasma levels of IL-6, TNF-alpha, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine (KC). Administration of rMIF protein also prevented E2-mediated reduction in neutrophil influx and tissue damage in the lungs following trauma-hemorrhage. These results suggest that the protective effects of E2 on lung injury following trauma-hemorrhage are mediated via downregulation of lung MIF and TLR4-induced cytokine/chemokine production.