BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis.
BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis.
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DOI：
10.1016/j.freeradbiomed.2022.06.005
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发表时间：
2022-08-01
影响因子：
7.4
通讯作者：
Raju, Raghavan Pillai
中科院分区：
文献类型：
--
作者：
Cai, Lun;Arbab, Ali S.;Lee, Tae Jin;Sharma, Ashok;Thomas, Bobby;Igarashi, Kazuhiko;Raju, Raghavan Pillai
脓毒症是由于宿主对感染的反应失调而引起的复杂疾病。氧化应激和线粒体功能障碍导致代谢失调是脓毒症的标志之一。转录因子NRF 2（Nuclear Factor E2-related faetor 2）是氧化应激反应的主要调节因子，并且NRF 2介导的抗氧化反应由BTB和CNC同源物1（BACH 1）蛋白负调节。本研究测试了Bach 1缺失是否改善盲肠结扎穿孔（CLP）诱导的多微生物脓毒症后的器官功能和存活率。我们观察到Bach 1 −/−小鼠CLP后生存率提高，同时肝脏HO-1表达增加，肝损伤和氧化应激减少，全身和组织炎症减轻。脓毒症诱导后，Bach 1 −/−小鼠的肝脏线粒体功能得到了更好的保护。此外，BACH 1缺陷改善败血症小鼠的肝和肺血流，如SPECT/CT所测量的。RNA-seq分析确定了44个基因在Bach 1 −/−小鼠脓毒症后发生了显著变化，包括HMOX 1和几个脂质代谢基因。通过锌原卟啉-9抑制HO-1活性会使Bach 1 −/−小鼠脓毒症后的器官功能恶化。我们证明，线粒体生物能量学，器官功能和实验性脓毒症后的生存率在Bach 1 −/−小鼠中通过HO-1依赖性机制得到改善，并得出结论，BACH 1是脓毒症的治疗靶点。
Sepsis is a complex disease due to dysregulated host response to infection. Oxidative stress and mitochondrial dysfunction leading to metabolic dysregulation are among the hallmarks of sepsis. The transcription factor NRF2 (Nuclear Factor E2-related faetor2) is a master regulator of the oxidative stress response, and the NRF2 mediated antioxidant response is negatively regulated by BTB and CNC homology 1 (BACH1) protein. This study tested whether Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). We observed enhanced post-CLP survival in Bach1−/− mice with a concomitantly increased liver HO-1 expression, reduced liver injury and oxidative stress, and attenuated systemic and tissue inflammation. After sepsis induction, the liver mitochondrial function was better preserved in Bach1−/− mice. Furthermore, BACH1 deficiency improved liver and lung blood flow in septic mice, as measured by SPECT/CT. RNA-seq analysis identified 44 genes significantly altered in Bach1−/− mice after sepsis, including HMOX1 and several genes in lipid metabolism. Inhibiting HO-1 activity by Zinc Protoporphyrin-9 worsened organ function in Bach1−/− mice following sepsis. We demonstrate that mitochondrial bioenergetics, organ function, and survival following experimental sepsis were improved in Bach1−/− mice through the HO-1-dependent mechanism and conclude that BACH1 is a therapeutic target in sepsis.
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DOI：
10.1164/rccm.201102-0271oc
发表时间：
2011-10-15
影响因子：
24.7
作者：
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影响因子：
2.2
作者：
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通讯作者：
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影响因子：
6.7
作者：
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