Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
J Immunol. 2014 Feb 15;192(4):1806-14. doi: 10.4049/jimmunol.1300835. Epub 2014 Jan 8.
Sepsis is a major cause of mortality, and dysregulation of the immune response plays a central role in this syndrome. H2S, a recently discovered gaso-transmitter, is endogenously generated by many cell types, regulating a number of physiologic processes and pathophysiologic conditions. We report that H2S increased survival after experimental sepsis induced by cecal ligation and puncture (CLP) in mice. Exogenous H2S decreased the systemic inflammatory response, reduced apoptosis in the spleen, and accelerated bacterial eradication. We found that C/EBP homologous protein 10 (CHOP), a mediator of the endoplasmic reticulum stress response, was elevated in several organs after CLP, and its expression was inhibited by H2S treatment. Using CHOP-knockout (KO) mice, we demonstrated for the first time, to our knowledge, that genetic deletion of Chop increased survival after LPS injection or CLP. CHOP-KO mice displayed diminished splenic caspase-3 activation and apoptosis, decreased cytokine production, and augmented bacterial clearance. Furthermore, septic CHOP-KO mice treated with H2S showed no additive survival benefit compared with septic CHOP-KO mice. Finally, we showed that H2S inhibited CHOP expression in macrophages by a mechanism involving Nrf2 activation. In conclusion, our findings show a protective effect of H2S treatment afforded, at least partially, by inhibition of CHOP expression. The data reveal a major negative role for the transcription factor CHOP in overall survival during sepsis and suggest a new target for clinical intervention, as well potential strategies for treatment.
脓毒症是导致死亡的主要原因，而免疫反应失调在该综合征中起着核心作用。H2S 是一种新发现的气体递质，由许多细胞类型内源性产生，调节许多生理过程和病理生理状况。我们报告说，H2S 增加了由盲肠结扎和穿刺（CLP）诱导的实验性脓毒症小鼠的存活率。外源性 H2S 降低了全身炎症反应，减少了脾脏中的细胞凋亡，并加速了细菌清除。我们发现，C/EBP 同源蛋白 10（CHOP），内质网应激反应的介质，在 CLP 后在几个器官中升高，并且其表达被 H2S 处理抑制。使用 CHOP 敲除（KO）小鼠，我们首次证明，据我们所知，CHOP 基因缺失增加了 LPS 注射或 CLP 后的存活率。CHOP-KO 小鼠显示脾 caspase-3 激活和凋亡减少，细胞因子产生减少，细菌清除增加。此外，与脓毒症 CHOP-KO 小鼠相比，用 H2S 治疗的脓毒症 CHOP-KO 小鼠没有额外的生存获益。最后，我们表明 H2S 通过 Nrf2 激活抑制巨噬细胞中 CHOP 的表达。总之，我们的发现表明 H2S 治疗的保护作用至少部分是通过抑制 CHOP 表达来实现的。这些数据揭示了转录因子 CHOP 在脓毒症期间总生存中的主要负作用，并为临床干预提供了一个新的靶点，以及潜在的治疗策略。
