Critical role of p38 MAPK for regeneration of the sciatic nerve following crush injury in vivo.
Critical role of p38 MAPK for regeneration of the sciatic nerve following crush injury in vivo.
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DOI：
10.1186/1742-2094-10-1
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发表时间：
2013-01-03
影响因子：
9.3
通讯作者：
Ogata M
中科院分区：
文献类型：
--
作者：
Kato N;Matsumoto M;Kogawa M;Atkins GJ;Findlay DM;Fujikawa T;Oda H;Ogata M
p38α（p38 MAPK 的同种型）的生理功能此前已在多项研究中使用药理学抑制剂进行了研究。然而，关于p38α在体内促进还是抑制神经再生的结果一直存在争议。我们生成了新型 p38α 突变小鼠（sem 小鼠），其编码 p38α 底物对接位点的区域具有点突变，可作为 p38α 的有限功能丧失模型。在本研究中，我们利用 sem 小鼠和野生型同窝小鼠（wt 小鼠）来研究 p38α 在挤压损伤后神经再生中的生理作用。挤压伤后4周，sem小鼠的平均轴突直径和平均轴突面积明显小于wt小鼠。与wt小鼠相比，sem小鼠的平均髓鞘厚度减少，但两组之间的G比没有观察到显着差异。坐骨神经功能指数值表明sem小鼠挤压伤后神经功能恢复延迟，这与组织学结果一致。为了研究这些发现的潜在机制，我们通过免疫组织化学和蛋白质印迹检查了坐骨神经的炎症反应。在挤压伤后的早期阶段，sem 小鼠的炎症细胞因子（如 TNF-α 和 IL-1β）的表达显着低于 wt 小鼠。 SEM 小鼠中 Caspase-3 和 Tenascin-C 的表达也较低。相反，在反应的后期，sem 小鼠的 TNF-α 和 IL-1β 表达显着高于 wt 小鼠，而 S-100 表达较低。这是第一个不依赖于使用药物抑制剂的 p38 MAPK 在神经再生中的生理作用的研究。我们的结果表明，p38α 不足可能会导致炎症性疾病，导致挤压伤后组织学和功能性神经恢复延迟。我们得出结论，p38 MAPK 在神经再生中具有重要的生理作用，并且可能对于控制炎症的发生和神经损伤的恢复很重要。
The physiological function of p38α, which is an isoform of p38 MAPK, has been investigated previously in several studies using pharmacological inhibitors. However, the results regarding whether p38α promotes or inhibits nerve regeneration in vivo have been controversial. We generated novel p38α mutant mice (sem mice) with a point mutation in the region encoding the p38α substrate-docking-site, which serves as a limited loss-of-function model of p38α. In the present study, we utilized sem mice and wild-type littermates (wt mice) to investigate the physiological role of p38α in nerve regeneration following crush injuries. At four weeks after crush injury, the average axon diameter and the average axon area in sem mice were significantly smaller than those in wt mice. The average myelin sheath thickness in sem mice was reduced compared to wt mice, but no significant difference was observed in the G-ratio between the two groups. The sciatic functional index value demonstrated that functional nerve recovery in sem mice following crush injury was delayed, which is consistent with the histological findings. To investigate the underlying mechanisms of these findings, we examined inflammatory responses of the sciatic nerve by immunohistochemistry and western blotting. At an early phase following crush injury, sem mice showed remarkably lower expression of inflammatory cytokines, such as TNF-α and IL-1β, than wt mice. The expression of Caspase-3 and Tenascin-C were also lower in sem mice. Conversely, at a late phase of the response, sem mice showed considerably higher expression of TNF-α and of IL-1β with lower expression of S-100 than wt mice. This is the first study of the physiological role of p38 MAPK in nerve regeneration that does not rely on the use of pharmacological inhibitors. Our results indicate that p38α insufficiency may cause an inflammatory disorder, resulting in a delay of histological and functional nerve recovery following crush injury. We conclude that p38 MAPK has an important physiological role in nerve regeneration and may be important for controlling both initiation of inflammation and recovery from nerve injury.
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影响因子：
3.5
作者：
Diem, R;Hobom, M;Bähr, M
通讯作者：
Bähr, M
DOI：
10.1007/bf01257247
发表时间：
1990-08-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
MARTINI, R;SCHACHNER, M;FAISSNER, A
通讯作者：
FAISSNER, A
影响因子：
3.3
作者：
Conti, G;De Pol, A;Scarlato, G
通讯作者：
Scarlato, G
影响因子：
2.9
作者：
Kato, N;Nemoto, K;Fujikawa, K
通讯作者：
Fujikawa, K
影响因子：
5.3
作者：
Mason, JL;Suzuki, K;Matsushima, GK
通讯作者：
Matsushima, GK