Traumatic Injury Activates MAP Kinases in Astrocytes: Mechanisms of Hypothermia and Hyperthermia
Traumatic Injury Activates MAP Kinases in Astrocytes: Mechanisms of Hypothermia and Hyperthermia
复制标题
DOI：
10.1089/neu.2008.0743
复制
发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Kuluz, John W.
中科院分区：
文献类型：
--
作者：
Huang, Tingting;Solano, Juan;Kuluz, John W.
高温是创伤性脑损伤(TBI)后常见的一种疾病，与神经系统预后不良有关。尽管其机制尚不清楚，但低温已成为治疗TBI的一种潜在有效方法。在这项研究中，我们研究了温度调节对创伤后星形胶质细胞存活的影响及其涉及的MAPK通路。创伤是通过培养的融合星形胶质细胞单层划痕损伤，然后在低温(30摄氏度)、常温(37摄氏度)或高温(39摄氏度)下孵育产生的。分别于伤后0、15、30、60、120min检测细胞外信号调节蛋白激酶(ERK)、c-jun氨基末端激酶(JNK)和p38MAPK的激活情况。用半胱氨酸天冬氨酸氨基转移酶-3(caspase-3)裂解定量检测损伤后24 h星形胶质细胞的凋亡。我们的研究结果表明，只有创伤后15分钟的JNK活性被低温降低，这与细胞凋亡的显著减少有关。高温可同时激活ERK和JNK，促进细胞凋亡。JNK特异性抑制剂SP60025在常温和高温条件下均能显著降低JNK诱导的细胞凋亡，并呈剂量依赖关系。综上所述，JNK通路似乎介导了创伤诱导的星形胶质细胞的凋亡。长期高温作为一种二次损伤，通过增加JNK的活性来恶化细胞凋亡。低温通过早期抑制JNK活性和随后阻止细胞凋亡来保护创伤性损伤。操纵星形胶质细胞中的JNK通路可能是改善脑创伤后组织损伤和细胞死亡的破坏性进展的治疗靶点。
Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30 degrees C), normothermia (37 degrees C), or hyperthermia (39 degrees C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120 min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24 h after injury. Our findings showed that only JNK activation at 15 min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.