Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis
Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis
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DOI：
10.1096/fj.06-6805com
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发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Hotchkiss, Richard S.
中科院分区：
文献类型：
--
作者：
Chang, Katherine C.;Unsinger, Jacqueline;Hotchkiss, Richard S.
淋巴细胞凋亡在脓毒症的病理生理学中起着核心作用。在由于 Fas 相关死亡结构域 (FADD-DN) 或 Bid(-/-) 的显性失活突变体的转基因表达而导致死亡受体途径缺陷的小鼠中，以及由于 Bim(-/-)、Puma(-/-) 或 Noxa(-/-) 丢失而导致线粒体介导途径缺陷的小鼠中，检查了淋巴细胞凋亡。 FADD-DN 转基因小鼠和 Bid(-/-) 小鼠具有显着但不完全的保护，并且这种保护与存活率的增加相关。令人惊讶的是，尽管转基因表达仅限于 T 细胞，但 FADD-DN 小鼠的脾 B 细胞也受到保护，这为间接保护机制提供了证据。 Bim(-/-) 对淋巴细胞凋亡提供了几乎完全的保护，而 Puma(-/-) 和 Noxa(-/-) 小鼠分别具有适度的保护或没有保护。 Bim(-/-) 小鼠的存活率有所提高，并且将 Bim(-/-) 小鼠的脾细胞过继转移到 Rag 1(-/-) 小鼠中证明这是淋巴细胞的内在效应。生存率的提高与白细胞介素 (IL) -10 和 IL-6 细胞因子的减少有关。总的来说，这些数据表明脓毒症期间会产生大量死亡刺激，因此阻断单个“触发因素”似乎不太可能抑制细胞凋亡。如果 siRNA 在治疗上变得实用，促凋亡蛋白将成为潜在的靶标。
Lymphocyte apoptosis plays a central role in the pathophysiology of sepsis. Lymphocyte apoptosis was examined in mice with defective death receptor pathways due to transgenic expression of a dominant negative mutant of Fas-associated death domain (FADD-DN) or Bid(-/-) and in mice with defective mitochondrial-mediated pathways due to loss of Bim(-/-), Puma(-/-), or Noxa(-/-). FADD-DN transgenic and Bid(-/-) mice had significant albeit incomplete protection, and this protection was associated with increased survival. Surprisingly, splenic B cells were also protected in FADD-DN mice although transgene expression was confined to T cells, providing evidence for an indirect protective mechanism. Bim(-/-) provided virtually complete protection against lymphocyte apoptosis whereas Puma(-/-) and Noxa(-/-) mice had modest or no protection, respectively. Bim(-/-) mice had improved survival, and adoptive transfer of splenocytes from Bim(-/-) mice into Rag 1(-/-) mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased interleukin (IL) -10 and IL-6 cytokines. Collectively, these data indicate that numerous death stimuli are generated during sepsis, and it therefore appears unlikely that blocking a single "trigger" can inhibit apoptosis. If siRNA becomes practical therapeutically, proapoptotic proteins would be potential targets.