Inhibition of autophagy with 3-methyladenine is protective in a lethal model of murine endotoxemia and polymicrobial sepsis

Here, the regulatory role of autophagy is examined in both an LPS-induced lethal endotoxic shock mouse model and cecal ligation and puncture (CLP) mouse model. Autophagy-inhibitor 3-methyladenine (3-MA) and autophagy-enhancer rapamycin were administrated to mice challenged with LPS or CLP. Animals challenged with LPS or CLP combined with 3-MA displayed increased survival after endotoxemia, but LPS combined with rapamycin worsened the endotoxic shock of the mice. Among the different organs studied, the lungs and intestines exhibited significant differences among LPS alone, LPS combined with 3-MA and LPS combined with rapamycin. LPS combined with 3-MA attenuated the inflammatory damages of these organs as compared with LPS alone. In contrast, LPS combined with rapamycin increased damage in these organs. Consistently, serum inflammatory mediators TNF-α and IL-6 were decreased by the treatment of LPS combined with 3-MA as compared with LPS alone, while administration of LPS combined with rapamycin increased the serum TNF-α and IL-6 levels. Similar results were found in mouse bone marrow-derived macrophages exposed to LPS. Moreover, the regulatory effect of autophagy to endotoxic shock is dependent on the TLR4 signaling pathway. Our results demonstrate the central role of autophagy in the regulation of endotoxic shock and its potential modulation for endotoxic shock treatment.

Download Full-text

Experimentally Approaching the ICU: Monitoring Outcome-Based Responses in the Two-Hit Mouse Model of Posttraumatic Sepsis

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/357926 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Susanne Drechsler ◽

Katrin M. Weixelbaumer ◽

Heinz Redl ◽

Martijn van Griensven ◽

Soheyl Bahrami ◽

...

Keyword(s):

Mouse Model ◽

Femur Fracture ◽

Cecal Ligation ◽

Blood Sampling ◽

Cecal Ligation And Puncture ◽

Organ Function ◽

Daily Monitoring ◽

Circulating Cells ◽

Facial Vein ◽

Insight Into

To simulate and monitor the evolution of posttraumatic sepsis in mice, we combined a two-hit model of trauma/hemorrhage (TH) followed by polymicrobial sepsis with repetitive blood sampling. Anesthetized mice underwent femur fracture/sublethal hemorrhage and cecal ligation and puncture (CLP) 48 h later. To monitor outcome-dependent changes in circulating cells/biomarkers, mice were sampled daily (facial vein) for 7 days and retrospectively divided into either dead (DIE) or surviving (SUR) by post-CLP day 7. Prior to CLP, AST was 3-fold higher in DIE, while all other post-TH changes were similar between groups. There was a significant post-CLP intergroup separation. In SUR, RBC and Hb were lower, platelets and neutrophils higher, and lymphocytes mixed compared to DIE. In DIE, all organ function markers except glucose (decrease) were few folds higher compared to SUR. In summary, the combination of daily monitoring with an adequate two-hit model simulates the ICU setting, allows insight into outcome-based responses, and can identify biomarkers indicative of death in the acute posttraumatic sepsis in mice.

Download Full-text

Protection from Lethal Cell Death in Cecal Ligation and Puncture-Induced Sepsis Mouse Model by In Vivo Delivery of FADD siRNA

Targets in Gene Therapy ◽

10.5772/19885 ◽

2011 ◽

Author(s):

Yuichi Hattori ◽

Naoyuki Matsu

Keyword(s):

Cell Death ◽

Mouse Model ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

In Vivo Delivery

Download Full-text

Contributory Role of BLT2 in the Production of Proinflammatory Cytokines in Cecal Ligation and Puncture-Induced Sepsis

Molecules and Cells ◽

10.14348/molcells.2021.0159 ◽

2021 ◽

Author(s):

Donghwan Park ◽

MyungJa Ro ◽

A-Jin Lee ◽

Dong-Wook Kwak ◽

Yunro Chung ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Cecal Ligation ◽

Cecal Ligation And Puncture

Download Full-text

Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6647258 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Jian Xie ◽

Zhen-zhen Zhao ◽

Peng Li ◽

Cheng-long Zhu ◽

Yu Guo ◽

...

Keyword(s):

Sleep Deprivation ◽

Cognitive Dysfunction ◽

Murine Model ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Signaling Proteins ◽

Cecal Ligation And Puncture ◽

Inflammatory Signaling ◽

Tnf Α ◽

Senkyunolide I

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

Download Full-text