Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury.
Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury.
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抑制 EGFR/MAPK 信号传导可减少脊髓损伤后大鼠的小胶质细胞炎症反应和相关的继发性损伤
DOI：
10.1186/1742-2094-9-178
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发表时间：
2012-07-23
影响因子：
9.3
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Qu WS;Tian DS;Guo ZB;Fang J;Zhang Q;Yu ZY;Xie MJ;Zhang HQ;Lü JG;Wang W
背景新的证据表明，小胶质细胞引发的炎症反应是原发性创伤性脊髓损伤（SCI）后继发性损伤的原因，表皮生长因子受体（EGFR）信号可能参与细胞活化。在这份报告中，我们调查的影响EGFR信号抑制小胶质细胞活化，促炎细胞因子的产生，和神经元微环境后sci. MethodsLipopolysaccharide处理的原代小胶质细胞/BV 2线细胞和SCI大鼠被用作模型系统。C225和AG 1478均用于抑制EGFR信号传导活化。荧光染色和Western blot检测细胞活化和EGFR磷酸化。采用逆转录PCR和ELISA法检测IL-1 β和TNFα的产生。Western blot半定量检测EGFR/磷酸化EGFR的表达及Erk、JNK和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。比较湿-干重以显示组织水肿。结果EGFR磷酸化与小胶质细胞活化平行，而EGFR阻断可抑制小胶质细胞活化相关的细胞形态学改变和IL-1β、TNFα的产生。EGFR阻断显著下调细胞活化后升高的MAPK活化;选择性MAPK抑制剂在一定程度上抑制细胞因子的产生，表明MAPK介导EGFR抑制剂对小胶质细胞活化的抑制。C225或AG 1478连续7天给药后，EGFR磷酸化表达、Erk和p38 MAPK磷酸化、IL-1β和TNFα的产生减少，小胶质细胞/星形胶质细胞活化、组织水肿和胶质瘢痕/空洞形成等继发性损伤减轻;结论抑制EGFR/MAPK可抑制小胶质细胞的活化和相关细胞因子的产生;减少神经炎症相关的继发性损伤，从而对SCI大鼠提供神经保护，这表明EGFR可能是治疗靶点，并且C225和AG 1478具有用于SCI治疗的潜力。
BackgroundEmerging evidence indicates that reactive microglia-initiated inflammatory responses are responsible for secondary damage after primary traumatic spinal cord injury (SCI); epidermal growth factor receptor (EGFR) signaling may be involved in cell activation. In this report, we investigate the influence of EGFR signaling inhibition on microglia activation, proinflammatory cytokine production, and the neuronal microenvironment after SCI.MethodsLipopolysaccharide-treated primary microglia/BV2 line cells and SCI rats were used as model systems. Both C225 and AG1478 were used to inhibit EGFR signaling activation. Cell activation and EGFR phosphorylation were observed after fluorescent staining and western blot. Production of interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNFα) was tested by reverse transcription PCR and ELISA. Western blot was performed to semi-quantify the expression of EGFR/phospho-EGFR, and phosphorylation of Erk, JNK and p38 mitogen-activated protein kinases (MAPK). Wet-dry weight was compared to show tissue edema. Finally, axonal tracing and functional scoring were performed to show recovery of rats.ResultsEGFR phosphorylation was found to parallel microglia activation, while EGFR blockade inhibited activation-associated cell morphological changes and production of IL-1β and TNFα. EGFR blockade significantly downregulated the elevated MAPK activation after cell activation; selective MAPK inhibitors depressed production of cytokines to a certain degree, suggesting that MAPK mediates the depression of microglia activation brought about by EGFR inhibitors. Subsequently, seven-day continual infusion of C225 or AG1478 in rats: reduced the expression of phospho-EGFR, phosphorylation of Erk and p38 MAPK, and production of IL-1β and TNFα; lessened neuroinflammation-associated secondary damage, like microglia/astrocyte activation, tissue edema and glial scar/cavity formation; and enhanced axonal outgrowth and functional recovery.ConclusionsThese findings indicate that inhibition of EGFR/MAPK suppresses microglia activation and associated cytokine production; reduces neuroinflammation-associated secondary damage, thus provides neuroprotection to SCI rats, suggesting that EGFR may be a therapeutic target, and C225 and AG1478 have potential for use in SCI treatment.
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表皮生长因子受体抑制通过血管正常化调节微环境，从而提高化疗和放疗疗效。
影响因子：
3.7
作者：
Cerniglia, George J.;Pore, Nabendu;Tsai, Jeff H.;Schultz, Susan;Mick, Rosemarie;Choe, Regine;Xing, Xiaoman;Durduran, Turgut;Yodh, Arjun G.;Evans, Sydney M.;Koch, Cameron J.;Hahn, Stephen M.;Quon, Harry;Sehgal, Chandra M.;Lee, William M. F.;Maity, Amit
通讯作者：
Maity, Amit
影响因子：
5.3
作者：
Gwak, Young S.;Unabia, Geda C.;Hulsebosch, Claire E.
通讯作者：
Hulsebosch, Claire E.
影响因子：
9.3
作者：
Bachstetter, Adam D.;Xing, Bin;Van Eldik, Linda J.
通讯作者：
Van Eldik, Linda J.
DOI：
10.1124/jpet.107.131060
发表时间：
2008-04-01
影响因子：
3.5
作者：
Genovese, Tiziana;Esposito, Emanuela;Cuzzocrea, Salvatore
通讯作者：
Cuzzocrea, Salvatore
DOI：
10.1097/00005072-198809000-00006
发表时间：
1988-09-01
影响因子：
3.2
作者：
BIRECREE, E;WHETSELL, WO;NANNEY, LB
通讯作者：
NANNEY, LB