Extracellular administration of BCL2 protein reduces apoptosis and improves survival in a murine model of sepsis.
Extracellular administration of BCL2 protein reduces apoptosis and improves survival in a murine model of sepsis.
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DOI：
10.1371/journal.pone.0014729
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发表时间：
2011-02-24
期刊：
影响因子：
3.7
通讯作者：
Harlan JM
中科院分区：
文献类型：
--
作者：
Iwata A;de Claro RA;Morgan-Stevenson VL;Tupper JC;Schwartz BR;Liu L;Zhu X;Jordan KC;Winn RK;Harlan JM
严重的败血症和感染性休克是世界范围内发病率和死亡率的主要原因。在实验性脓毒症中，存在各种细胞类型的显著凋亡，死亡和生存途径的基因操纵已被证明调节器官损伤和生存。在盲肠结扎穿孔(CLP)诱导的小鼠脓毒症模型中，我们研究了细胞内死亡调节因子BCL2(B细胞淋巴瘤2)家族的两个抗凋亡成员细胞外给药的效果。我们发现，根据死亡的替代标记物的评估，腹腔注射皮考莫尔范围内剂量的重组人(Rh)BCL2或重组人BCL2A1蛋白显著提高了存活率。应用重组人BCL2或重组人BCL2A1蛋白可显著减少CLP后肠道和心脏的细胞凋亡率，并伴随着内源性BCL2蛋白表达的增加。此外，接受重组人BCL2A1蛋白治疗的小鼠在CLP后腹膜中性粒细胞总数增加，中性粒细胞凋亡减少。最后，尽管BCL2和BCL2A1都不是直接的TLR2配体，但TLR2缺失的小鼠不受rhBCL2A1蛋白的保护，这表明体内细胞外给药的BCL2A1蛋白的保护活性需要TLR2信号。用rh BCL2A1或rh BCL2蛋白治疗通过减少多个靶组织中的细胞凋亡来保护小鼠免受脓毒症的侵袭，展示了细胞外给予BCL2 BH4结构域蛋白的意想不到的、有效的活性。
Severe sepsis and septic shock are major causes of morbidity and mortality worldwide. In experimental sepsis there is prominent apoptosis of various cell types, and genetic manipulation of death and survival pathways has been shown to modulate organ injury and survival. We investigated the effect of extracellular administration of two anti-apoptotic members of the BCL2 (B-cell lymphoma 2) family of intracellular regulators of cell death in a murine model of sepsis induced by cecal ligation and puncture (CLP). We show that intraperitoneal injection of picomole range doses of recombinant human (rh) BCL2 or rhBCL2A1 protein markedly improved survival as assessed by surrogate markers of death. Treatment with rhBCL2 or rhBCL2A1 protein significantly reduced the number of apoptotic cells in the intestine and heart following CLP, and this was accompanied by increased expression of endogenous mouse BCL2 protein. Further, mice treated with rhBCL2A1 protein showed an increase in the total number of neutrophils in the peritoneum following CLP with reduced neutrophil apoptosis. Finally, although neither BCL2 nor BCL2A1 are a direct TLR2 ligand, TLR2-null mice were not protected by rhBCL2A1 protein, indicating that TLR2 signaling was required for the protective activity of extracellularly adminsitered BCL2A1 protein in vivo. Treatment with rhBCL2A1 or rhBCL2 protein protects mice from sepsis by reducing apoptosis in multiple target tissues, demonstrating an unexpected, potent activity of extracellularly administered BCL2 BH4-domain proteins.
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DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
6.7
作者：
Hatada, T;Wada, H;Maruyama, I
通讯作者：
Maruyama, I
影响因子：
4.4
作者：
Iwata, A;Stevenson, VM;Winn, RK
通讯作者：
Winn, RK
DOI：
10.1073/pnas.1031788100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Hotchkiss, RS;Chang, KC;Karl, IE
通讯作者：
Karl, IE
影响因子：
38.9
作者：
Hagiwara, Satoshi;Iwasaka, Hideo;Noguchi, Takayuki
通讯作者：
Noguchi, Takayuki