Blocking Liver Autophagy Accelerates Apoptosis and Mitochondrial Injury in Hepatocytes and Reduces Time to Mortality in a Murine Sepsis Model

Shock
Takehiko OamiShigeto Oda

Abstract

Autophagy plays an important role in cell survival, sequestering, and degrading a wide variety of substrates. Although an increase of autophagosomes in liver has been reported in sepsis patients as well as in septic mice, the influence of autophagy on liver injury, the interaction between autophagy, and other types of cell death in sepsis remain unclear. The aim of this study was to elucidate the contribution of liver autophagy to the pathophysiology of sepsis. We performed a cecal ligation and puncture on liver-specific autophagy-deficient (Alb-Cre/Atg5) mice (6-8-week-old male). When compared with controls (C57BL/6), we found a significant accumulation of p62 in the liver and demonstrated a greater number of cleaved caspase-3 immunoreactive hepatocytes in these knockout (KO) mice. Additionally, we confirmed a significant increase in autophagic vacuoles in the control mice relative to KO mice; in contrast, cell shrinkage and nuclear fragmentation (morphological characteristics of apoptosis) were preferentially seen in the KO mice by transmission electron microscopy. Severe mitochondrial damage was also prominent in KO mice, relative to controls, associated with an increase of reactive oxygen species in hepatocytes. Serum aspar...Continue Reading

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Citations

Sep 15, 2018·Shock·Hiroyuki Hirasawa
Jan 22, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shihong WenWenqi Huang
Mar 17, 2020·EMBO Molecular Medicine·Jean-Marc CavaillonTomasz Skirecki
Sep 12, 2019·Frontiers in Physiology·Xin YinLiheng Guo
Aug 15, 2019·Experimental and Therapeutic Medicine·Fei WangZuowei Pei
Oct 2, 2020·Cell Death & Disease·Sheng-Yu ZhuYong-Ming Yao
Feb 16, 2021·World Journal of Hepatology·Elias KouroumalisDimitrios N Samonakis
Jan 1, 2021·BioMed Research International·Qian-Wei LiXiao-Qing Zhang

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