Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis

Takahashi, Waka; Watanabe, Eizo; Fujimura, Lisa; Watanabe-Takano, Haruko; Yoshidome, Hiroyuki; Swanson, Paul E.; Tokuhisa, Takeshi; Oda, Shigeto; Hatano, Masahiko

doi:10.1186/cc12839

Cited by 115 publications

(100 citation statements)

References 48 publications

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“…51 Conversely, administration of chloroquine abolishes autophagic flux, which results in the elevation of serum transaminase levels. 14 Compelling evidence confirms that autophagy in the liver is induced during the initial 4 h after CLP but declines after this point until 24 h. 11,14,19,36,51 The blockade of autophagic flux is demonstrated by reduced LAMP1 expression, accumulation of SQSTM1 and lack of colocalization of autophagosomes with lysosomes.…”

Section: Livermentioning

confidence: 74%

“…During the initial 4 to 6 h after CLP, hepatocytes and cardiomyocytes show a considerably higher LC3-II:LC3-I ratio (a marker of autophagy induction), accompanied by an increased number of autophagosomes. 11,14 However, the autolysosomal (the product of an autophagosome fusing with a lysosome) numbers decrease from 8 h onwards, leading to accumulation of SQSTM1/p62 receptor proteins. Survival of mice is increased by administration of carbamazepine, an autophagic flux modulator, as evidenced by an increase in LC3-II, RAB7 and a decreased level of the receptor protein SQSTM1.…”

Section: Kinetics Of Autophagy In Sepsismentioning

confidence: 99%

“…33,34 Accumulating evidence shows that autophagic activity is elevated during the hyperdynamic phase of sepsis followed by a decline. 11,14,35,36 Cecal ligation and puncture (CLP)-induced peritonitis using C56BL/6 mice is the most widely used animal model of sepsis. During the initial 4 to 6 h after CLP, hepatocytes and cardiomyocytes show a considerably higher LC3-II:LC3-I ratio (a marker of autophagy induction), accompanied by an increased number of autophagosomes.…”

Section: Kinetics Of Autophagy In Sepsismentioning

confidence: 99%

“…8 Further ex vivo experiments revealed that the mRNA expression of IRGM is significantly lower in the TT genotype, rendering it defective in autophagy. 8 Accumulating evidence from in vitro and in vivo studies [9][10][11][12][13][14][15] suggest that autophagy plays a protective role in sepsis, although contradictory findings have been reported. 16,17 In support of this notion, newly tested therapeutic agents in animal models have targeted modulation of the same molecular pathway-autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

127

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Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

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Section: Livermentioning

confidence: 74%

Section: Kinetics Of Autophagy In Sepsismentioning

confidence: 99%

Section: Kinetics Of Autophagy In Sepsismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

127

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“…Autophagy is activated in sepsis and exerts a protective role, by maintaining cellular homeostasis and limiting cell damage and death (20,21). Previous studies have demonstrated that autophagy protects against sepsis-induced apoptotic cell death in the liver (22,23) and kidney (24,25), as well as lung injury (26,27) and immune systems (9,10).…”

Section: Clinical Application: Restoration Of Immune Homeostasis By Amentioning

confidence: 99%

Clinical application: Restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis

Zhang

Tsung

2016

Experimental and Therapeutic Medicine

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Abstract. Sepsis-induced lymphocyte and dendritic cell apoptosis contributes to immunosuppression, resulting in an inability to eradicate the primary infection and a propensity to acquire secondary infections. However, the inhibition of apoptosis may produce unexpected and undesirable consequences. Another cellular process, autophagy, is also activated in immune cells. There is increasing evidence to suggest that autophagy confers a protective effect in sepsis. The protective mechanisms underlying this effect include limiting apoptotic cell death and maintaining cellular homeostasis. Therefore, understanding the regulation of immune cell autophagy and apoptosis may provide insight into novel therapeutic strategies. The present review examined potential novel therapeutic strategies aimed at restoring immune homeostasis by inducing autophagy. The restoration of balance between apoptosis and autophagy may be a novel approach for improving sepsis-induced immunosuppression and decreasing susceptibility to sepsis. Contents1. Introduction 2. Immune cell apoptosis in sepsis 3. Immune cell autophagy in sepsis 4. Regulation immunity and inflammation 5. Reciprocal regulation between apoptosis and autophagy 6. Autophagy as a therapeutic target in pulmonary diseases 7. Autophagy as a potential therapeutic target for sepsis 8. Conclusion IntroductionDespite major advances in critical care management and antibiotic therapies, sepsis-induced multiple organ failure (MOF) continues to contribute to significant morbidity and mortality in intensive care units (ICUs) (1). MOF is the second leading cause of death among patients in non-coronary ICUs, and the tenth leading cause of death in the United States (2). In the United States, an estimated 250,000 individuals succumb to sepsis every year. The incidence of sepsis is increasing at a rate of 1.5% per annum and mortality rates of ≤70% have been estimated (3). Furthermore, this mortality rate has remained essentially unchanged for the past 25 years (2,4).Treating patients with severe sepsis and septic shock has been a great challenge. This is due to the incomplete understanding of the complex biological processes underlying sepsis, which has hindered the development of sepsis-specific therapies (1). Thus, it is essential to determine the mechanism underlying the pathophysiology of sepsis so that more effective therapeutic strategies may be developed.Traditionally, sepsis has been considered to be an overwhelming inflammatory response, which results in MOF from which the patient ultimately succumbs (1). However, over the past 25 years, numerous clinical trials involving agents that block the inflammatory cascade, such as anti-endotoxin antibodies (5), interleukin-1 (IL-1) receptor antagonists (6), and tumor necrosis factor-α (TNF-α) antagonists (7), have failed to improve the outcome of sepsis. The failure of anti-inflammatory agents highlights the fact that further research is required in order to elucidate the mechanisms underlying the septic response.Numerous mechanisms underlie s...

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Fat‐1 transgenic mice rich in endogenous omega‐3 fatty acids are protected from lipopolysaccharide‐induced cardiac dysfunction

Mao

Ma²,

Chen

et al. 2021

ESC Heart Failure

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Aims Cardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous ω-3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous ω-3 PUFA in transgenic fat-1 mice would alleviate the lipopolysaccharide (LPS)-induced cardiac failure and death. Methods and results After both wild type (WT) and transgenic fat-1 mice were challenged with LPS, a Kaplan-Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT-PCR, western blotting, immune-histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat-1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat-1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS-challenged fat-1 mice demonstrated the significantly lower levels of pro-inflammatory markers and ROS than WT mice. Meaningfully, the LPS-treated fat-1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS-treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator-activated receptor (PPAR) γ and sirtuin (Sirt)-1 expression, associated with a parallel decrease in NFκB activation. Conclusions The fat-1 mice were protected from the detrimental LPS-induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt-1 and PPARγ signals.

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Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis

Cited by 115 publications

References 48 publications

Autophagy in sepsis: Degradation into exhaustion?

Autophagy in sepsis: Degradation into exhaustion?

Clinical application: Restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis

Fat‐1 transgenic mice rich in endogenous omega‐3 fatty acids are protected from lipopolysaccharide‐induced cardiac dysfunction

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