Abstract

BackgroundSepsis with brain dysfunction has contributed to an increase risk of morbidity and mortality. In its pathophysiology, both autophagy and nuclear factor κB (NF-κB) have been suggested to play important roles. Based on the fact that crosstalk between autophagy and NF-κB, two stress-response signaling pathways, has been detected in other pathophysiological processes, this study was undertaken to explore the process of autophagy in the hippocampus of septic rats and the role NF-κB plays in the regulation of autophagy during the process.MethodsCecal ligation and puncture (CLP) or a sham operation was conducted on male Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of the NF-κB signaling pathway, or a vehicle control, was used to treat with the rats 2 h before the CLP operation. Hematoxylin-eosin staining and biological signal recording was used to measure the morphological and physiological signs of hippocampal dysfunction. An electron microscope was used to observe autophagosome formation and lysosome activation in the hippocampus after CLP. Western blotting and immune histochemistry were used to detect the hippocampus levels of NF-κB and essential proteins involved in formation of the autophagosome (microtubule-associated protein light chain 3 (LC3), Beclin1, Lamp-1, and Rab7).ResultsCompared with sham-operated rats, the CLP rats showed decreasing mean arterial pressure (MAP), increasing heart rate (HR), and pathological histological changes. CLP rats exhibited not only increased vacuolization through electron micrographs but also increased LC3-II, decreased Beclin1, LAMP-1, and Rab7 through the immunofluorescence and Western blot. However, PDTC + CLP rats revealed that inhibition of the NF-κB signal axis by PDTC increased the levels of LC3-II, Beclin1, LAMP-1, and Rab7 and improved physiological function including blood pressure and heart rate.ConclusionsThe autophagy process during the hippocampus of CLP rats might be blocked by the activation of NF-κB signaling pathway. Inhibition of NF-κB signaling pathway could enhance the completion of autophagy with a neuroprotective function in septic brains.

Highlights

  • Sepsis with brain dysfunction has contributed to an increase risk of morbidity and mortality

  • It can be concluded that the mean arterial pressure (MAP) level was strikingly higher (P < 0.05) in the Pyrrolidine dithiocarbamate (PDTC) + Cecal ligation and puncture (CLP) groups than in the CLP groups and that the heart rate (HR) level was notably lower (P < 0.05) in the PDTC + CLP groups than in the CLP groups (Table 2)

  • Our study demonstrates for the first time that autophagy is induced in the hippocampus during CLPinduced sepsis

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Summary

Introduction

Sepsis with brain dysfunction has contributed to an increase risk of morbidity and mortality. In its pathophysiology, both autophagy and nuclear factor κB (NF-κB) have been suggested to play important roles. Based on the fact that crosstalk between autophagy and NF-κB, two stress-response signaling pathways, has been detected in other pathophysiological processes, this study was undertaken to explore the process of autophagy in the hippocampus of septic rats and the role NF-κB plays in the regulation of autophagy during the process. Autophagy has been suggested to play an important role in the pathophysiology of sepsis [10,11,12]. The relationship between autophagy and brain disorder occurring with sepsis remains unclear [20, 21]

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