Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion.
Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion.
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DOI：
10.1186/1742-2094-9-169
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发表时间：
2012-07-11
影响因子：
9.3
通讯作者：
Faden AI
中科院分区：
文献类型：
--
作者：
Wu J;Pajoohesh-Ganji A;Stoica BA;Dinizo M;Guanciale K;Faden AI
创伤性脊髓损伤(SCI)导致继发性组织损伤，与星形胶质细胞增生症和炎症相关。我们以前曾报道，一组细胞周期相关基因的急性上调导致了有丝分裂后细胞死亡和脊髓损伤后的继发性损伤。然而，目前尚不清楚细胞周期激活是否更长期地持续，并导致更多延迟的胶质细胞变化。在这里，我们研究了脊髓损伤后长达4个 月的细胞周期相关蛋白的表达，以及选择性细胞周期蛋白依赖性激酶(CDKs)抑制剂CR8对大鼠脊髓挫伤模型星形胶质细胞增生和小胶质细胞激活的影响。成年雄性大鼠在T8时采用典型的体重下降模型造成中度脊髓挫伤。于损伤后4 周或4 个月取损伤中心组织，进行蛋白质表达和损伤体积分析。在伤后4个 月内评定功能恢复情况。免疫印迹分析显示，细胞周期相关蛋白 − 在损伤后4个月持续上调，主要表达于星形胶质细胞和小胶质细胞，并与炎症相关蛋白共定位。损伤后4个月，细胞周期相关蛋白Cyclin D1、E、CDK4、E2F5和增殖细胞核抗原 − 持续上调。伤后3 h全身应用CR8，持续7 d，可抑制脊髓损伤后4个月内细胞周期蛋白的持续升高及 − 、Iba-1和p22PHOX − 的免疫反应。p22PHOX是NADPH氧化酶 的重要组成部分。CR8治疗显著减少了损伤体积，这通常发生在创伤后1至4个 月未经治疗的动物身上。从第2周到第16周，CR8治疗也显著促进了脊髓损伤后功能的恢复。这些数据表明，细胞周期相关蛋白在脊髓损伤后慢性上调，可能与星形胶质细胞瘢痕形成、慢性炎症和进一步的组织丢失有关。
Traumatic spinal cord injury (SCI) induces secondary tissue damage that is associated with astrogliosis and inflammation. We previously reported that acute upregulation of a cluster of cell-cycle-related genes contributes to post-mitotic cell death and secondary damage after SCI. However, it remains unclear whether cell cycle activation continues more chronically and contributes to more delayed glial change. Here we examined expression of cell cycle-related proteins up to 4 months following SCI, as well as the effects of the selective cyclin-dependent kinase (CDKs) inhibitor CR8, on astrogliosis and microglial activation in a rat SCI contusion model. Adult male rats were subjected to moderate spinal cord contusion injury at T8 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 weeks or 4 months post-injury, and processed for protein expression and lesion volume. Functional recovery was assessed over the 4 months after injury. Immunoblot analysis demonstrated a marked continued upregulation of cell cycle-related proteins − including cyclin D1 and E, CDK4, E2F5 and PCNA − for 4 months post-injury that were highly expressed by GFAP+ astrocytes and microglia, and co-localized with inflammatory-related proteins. CR8 administrated systemically 3 h post-injury and continued for 7 days limited the sustained elevation of cell cycle proteins and immunoreactivity of GFAP, Iba-1 and p22PHOX − a key component of NADPH oxidase − up to 4 months after SCI. CR8 treatment significantly reduced lesion volume, which typically progressed in untreated animals between 1 and 4 months after trauma. Functional recovery was also significantly improved by CR8 treatment after SCI from week 2 through week 16. These data demonstrate that cell cycle-related proteins are chronically upregulated after SCI and may contribute to astroglial scar formation, chronic inflammation and further tissue loss.
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影响因子：
4.2
作者：
Kabadi, Shruti V.;Stoica, Bogdan A.;Faden, Alan I.
通讯作者：
Faden, Alan I.
影响因子：
5.3
作者：
Jakovcevski, Igor;Wu, Junfang;Schachner, Melitta
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影响因子：
11.4
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影响因子：
5.3
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WRATHALL, JR
影响因子：
6.2
作者：
Byrnes, KR;Garay, J;Faden, AI
通讯作者：
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