Insufficient Activation of Autophagy Allows Cellular Damage to Accumulate in Critically Ill Patients

Vanhorebeek, Ilse; Gunst, Jan; Derde, Sarah; Derese, Inge; Boussemaere, Magaly; Güiza, Fabián; Martinet, Wim; Timmermans, Jean‐Pierre; D’Hoore, André; Wouters, Pieter; Berghe, Greet Van den

doi:10.1210/jc.2010-2563

Cited by 188 publications

(123 citation statements)

References 47 publications

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“…Autophagy signaling is not normal in critically ill patients (28), therefore regulation is a potential therapeutic target to improve for disease treatment. The synthesized peptide Tatbeclin-1 induces the autophagy process; mice treated with Tat-beclin-1 were resistant to several infectious diseases (29).…”

Section: Discussionmentioning

confidence: 99%

Hepatic autophagy after severe burn in response to endoplasmic reticulum stress

Song¹,

Libero²,

Wolf³

2014

Journal of Surgical Research

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Introduction Previous studies showed liver dysfunction after severe burn, and that this is associated with activation of endoplasmic reticulum (ER) stress. Autophagy is a catabolic process to maintain cellular organelle balance; ER stress is associated with autophagy signaling cascades. We thus sought to determine whether autophagy signals were associated with damage in the liver after burn, and further whether burn associated ER stress activates autophagy signals in hepatocytes. Methods C57BL6 male mice received a 25% total body surface area full thickness (TBSA) scald burn, and liver was harvested at 24 hours after burn. HepG2 cells were stimulated with an ER stress inducer thapsigargin (TG) for 24 hours to mimic ER stress in vitro. TUNEL staining was performed on liver histology sections. Autophagy was assessed by immunoblotting. Statistical analysis was by Student’s t-test and significance was accepted at p<0.05. Results TUNEL positive stained hepatocytes increased in burned animals with a significant elevation of caspase 3 activity (p<0.05). A marked increase in hepatic ATG3, ATG5 and LC3B was detected as well (p<0.05). Expression of Beclin-1, LC3A and LC3B increased in HepG2 cells in response to TG, similar to the response seen in vivo. Cytosolic ATP dropped significantly, and AMPK and mTOR were phosphorylated as well in response to TG (p<0.05). Conclusion ER stress, which occurs in hepatocytes after severe injury, is associated with autophagy and liver damage following severe burn. In response to ER stress, activated autophagy is associated with AMPK/mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

Hepatic autophagy after severe burn in response to endoplasmic reticulum stress

Song¹,

Libero²,

Wolf³

2014

Journal of Surgical Research

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“…An analysis that examined liver and skeletal muscle from critically ill patients utilized tissue biopsies that were taken within 30 ± 20 min after death and were flash-frozen in liquid nitrogen followed by storage at -80°C. 815 Samples could subsequently be used for EM and western blot analysis.…”

Section: 792mentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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“…Indeed, we demonstrated a reduction of triglyceride content in non-adipose tissues, such as liver and skeletal muscle, a reduction which was even more pronounced with nutrient restriction. Our observation of triglyceride reduction in liver does not contradict the known occurrence of fatty liver in critically ill patients, because our mouse model was well controlled for hyperglycemia, which is a major trigger for hepatic steatosis during critical illness [29,30]. …”

Section: Discussionmentioning

confidence: 81%

Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages

Marques¹,

Perre²,

Aertgeerts³

et al. 2013

Critical Care

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IntroductionWe previously reported that in artificially-fed critically ill patients, adipose tissue reveals an increase in small adipocytes and accumulation of M2-macrophages. We hypothesized that nutrient-independent factors of critical illness explain these findings, and that the M2-macrophage accumulation may not be limited to adipose tissue.MethodsIn a long-term cecal ligation and puncture (CLP) mouse model of sepsis, we compared the effect of parenteral nutrition (CLP-fed, n = 13) with nutrient restriction (CLP-restricted, n = 11) on body composition, adipocyte size and macrophage accumulation in adipose tissue, liver and lungs. Fed healthy mice (n = 11) were studied as controls. In a human study, in vivo adipose tissue biopsies were studied from ICU patients (n = 40) enrolled in a randomized control trial which compared early initiation of parenteral nutrition (PN) versus tolerating nutrient restriction during the first week of ICU stay. Adipose tissue morphology was compared with healthy human controls (n = 13).ResultsIrrespective of nutritional intake, critically ill mice lost weight, fat and fat-free mass. Adipocyte number, proliferation marker Proliferating Cell Nuclear Antigen (PCNA) and adipogenic markers PPARγ and CCAAT/enhancer binding protein-β (C/EBPβ) increased with illness, irrespective of nutritional intake. M2-macrophage accumulation was observed in adipose tissue, liver and lungs of critically ill mice. Macrophage M2-markers correlated with CCL2 expression. In adipose tissue biopsies of critically ill patients, increased adipogenic markers and M2 macrophage accumulation were present irrespective of nutritional intake.ConclusionsAdipogenesis and accumulation of tissue M2-macrophages are hallmarks of prolonged critical illness, irrespective of nutritional management. During critical illness, M2-macrophages accumulate not only in adipose tissue, but also in the liver and lungs.

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Insufficient Activation of Autophagy Allows Cellular Damage to Accumulate in Critically Ill Patients

Cited by 188 publications

References 47 publications

Hepatic autophagy after severe burn in response to endoplasmic reticulum stress

Hepatic autophagy after severe burn in response to endoplasmic reticulum stress

Guidelines for the use and interpretation of assays for monitoring autophagy

Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages

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