Role of the TLR4 pathway in blood-spinal cord barrier dysfunction during the bimodal stage after ischemia/reperfusion injury in rats.
Role of the TLR4 pathway in blood-spinal cord barrier dysfunction during the bimodal stage after ischemia/reperfusion injury in rats.
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DOI：
10.1186/1742-2094-11-62
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发表时间：
2014-03-28
影响因子：
9.3
通讯作者：
Ma H
中科院分区：
文献类型：
--
作者：
Li XQ;Lv HW;Tan WF;Fang B;Wang H;Ma H
脊髓缺血-再灌注（I/R）涉及两个阶段的损伤，包括初始急性缺血性损伤和随后的炎性再灌注损伤，导致涉及TLR 4通路的血-脊髓屏障（BSCB）功能障碍。然而，BSCB功能障碍中TLR 4/MyD 88依赖性和TLR 4/TRIF依赖性途径之间的相关性尚未完全了解。本研究的目的是描述脊髓I/R中的炎症反应和定义其临床进展的事件，延迟神经功能缺损，支持损伤的双峰机制。在阻断主动脉弓14分钟前，每隔12 h鞘内注射TAK-242、MyD 88抑制肽或白藜芦醇3 d。在再灌注后6、12、18、24、36、48和72 h检测伊文思蓝（EB）外渗和含水量。再灌注后EB渗出量、含水量和NF-κB活化均随时间推移而增加，呈双峰分布，在再灌注后12和48 h达到最大增加。这些变化与通过Western blot测定的TLR 4水平成正比。采用免疫组化双标记法检测不同类型BSCB细胞与TLR 4的关系。此外，在12和48 h分析NF-κB和IL-1β以鉴定MyD 88依赖性和TRIF依赖性途径之间的相关性。无TLR 4和MyD 88的大鼠在12 h时可减弱BSCB渗漏和炎症反应，表明缺血事件在很大程度上是由MyD 88依赖性通路介导的。在TLR 4、MyD 88和TRIF受体缺失的大鼠中观察到的类似保护作用在48 h时推断，发生在晚期的持续炎症主要由TRIF依赖性通路启动，并且这种炎症反应可以通过MyD 88依赖性通路进一步放大。此外，小胶质细胞似乎在I/R损伤后的早期炎症反应中起主要作用，而在晚期反应阶段，小胶质细胞和星形胶质细胞都是必需的。这些发现表明TLR 4/MyD 88依赖性和TLR 4/TRIF依赖性途径在I/R损伤后炎症反应的双峰阶段中的相关性，与损伤的临床进展和症状的延迟发作相对应。TLR 4信号抑制剂在不同阶段的临床应用可能是预防迟发性损伤的一种治疗选择。
Spinal cord ischemia-reperfusion (I/R) involves two-phase injury, including an initial acute ischemic insult and subsequent inflammatory reperfusion injury, resulting in blood-spinal cord barrier (BSCB) dysfunction involving the TLR4 pathway. However, the correlation between TLR4/MyD88-dependent and TLR4/TRIF-dependent pathways in BSCB dysfunction is not fully understood. The aim of this study is to characterize inflammatory responses in spinal cord I/R and the events that define its clinical progression with delayed neurological deficits, supporting a bimodal mechanism of injury. Rats were intrathecally pretreated with TAK-242, MyD88 inhibitory peptide, or Resveratrol at a 12 h interval for 3 days before undergoing 14-minute occlusion of aortic arch. Evan’s Blue (EB) extravasation and water content were detected at 6, 12, 18, 24, 36, 48, and 72 h after reperfusion. EB extravasation, water content, and NF-κB activation were increased with time after reperfusion, suggesting a bimodal distribution, as maximal increasing were detected at both 12 and 48 h after reperfusion. The changes were directly proportional to TLR4 levels determined by Western blot. Double-labeled immunohistochemical analysis was also used to detect the relationship between different cell types of BSCB with TLR4. Furthermore, NF-κB and IL-1β were analyzed at 12 and 48 h to identify the correlation between MyD88-dependent and TRIF-dependent pathways. Rats without functional TLR4 and MyD88 attenuated BSCB leakage and inflammatory responses at 12 h, suggesting the ischemic event was largely mediated by MyD88-dependent pathway. Similar protective effects observed in rats with depleted TLR4, MyD88, and TRIF receptor at 48 h infer that the ongoing inflammation which occurred in late phase was mainly initiated by TRIF-dependent pathway and such inflammatory response could be further amplified by MyD88-dependent pathway. Additionally, microglia appeared to play a major role in early phase of inflammation after I/R injury, while in late responding phase both microglia and astrocytes were necessary. These findings indicate the relevance of TLR4/MyD88-dependent and TLR4/TRIF-dependent pathways in bimodal phases of inflammatory responses after I/R injury, corresponding with the clinical progression of injury and delayed onset of symptoms. The clinical usage of TLR4 signaling inhibitors at different phases may be a therapeutic option for the prevention of delayed injury.
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影响因子：
4.3
作者：
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