Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3
Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3
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DOI：
10.1371/journal.pone.0001605
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发表时间：
2008-02-13
期刊：
影响因子：
3.7
通讯作者：
Tweardy, David J.
中科院分区：
文献类型：
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作者：
Alten, Jeffrey A.;Moran, Ana;Tweardy, David J.
一半的创伤死亡归因于低血容量循环衰竭（HCC）。我们在涉及轻微创伤和严重失血性休克（HS）的大鼠中建立了 HCC 模型。该模型中的 HCC 伴随着主动脉血流峰值加速度和心肌细胞凋亡减少 50%。 HCC 和细胞凋亡随着低血压持续时间的增加而增加。细胞凋亡需要复苏，这提供了治疗干预的机会。给予IL-6可完全逆转HCC，预防心脏功能障碍和心肌细胞凋亡，使死亡率降低5倍，并激活心内信号转导器和转录激活子（STAT）3。用Stat3的选择性抑制剂T40214预处理大鼠，减少IL-6介导的心脏Stat3活性增加，阻止IL-6成功复苏并逆转IL-6介导的心脏细胞凋亡保护。缺乏天然存在的 Stat3 显性失活亚型（Stat3 beta）的小鼠心脏对 HS 诱导的细胞凋亡具有完全抵抗力。针对细胞凋亡相关基因的心脏微阵列分析显示，与假手术大鼠相比，HS 大鼠中 29% 的细胞凋亡相关基因的表达发生了改变。 IL-6 处理使这些基因的表达正常化，而 T40214 预处理则阻止 IL-6 介导的正常化。因此，心功能障碍、心肌细胞凋亡和凋亡途径基因的诱导是HCC的重要组成部分； IL-6 给药通过阻断心肌细胞凋亡和通过 Stat3 诱导凋亡途径基因来预防 HCC，并且值得进一步研究作为预防创伤患者 HCC 和死亡的复苏佐剂。
Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3 beta, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients.