Sepsis: in search of cure

Lakshmikanth, Chikkamenahalli Lakshminarayana; Jacob, Shancy Petsel; Chaithra, Vyala Hanumanthareddy; Castro‐Faria‐Neto, Hugo C.; Marathe, Gopal K.

doi:10.1007/s00011-016-0937-y

Cited by 60 publications

(43 citation statements)

References 204 publications

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“…The induced inflammatory response usually becomes severe and uncontrolled in a relatively short time, leading to acute organ dysfunction and other systemic disorders [23]. Despite progress in medical care and treatment, the morbidity of sepsis increases annually and the mortality remains remarkably high [24].…”

Section: Discussionmentioning

confidence: 99%

Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway

Kuang

Cen

Qin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lipopolysaccharide (LPS) plays a critical role in excessive inflammatory cytokine production during sepsis. Previously, artesunate (AS) was reported to protect septic mice by reducing LPS-induced pro-inflammatory cytokine release. In the present study, the possible mechanism of the anti-inflammatory effect of AS was further investigated. Methods: An enzyme-linked immunosorbent assay was used to detect TNF-α and IL-6 release from macrophages. Specific small interfering RNAs (siRNAs) were used to knockdown the mRNA expression of target genes. Transmission electron microscopy and laser confocal microscopy were used to observe changes in autophagy. Western blotting was performed to detect the protein levels of tumor necrosis factor receptor-associated factor6 (TRAF6), Beclin1, phosphatidylinositol 3-kinase class III (PI3KC3), autophagy-related protein 5 (ATG5), and sequestosome 1. Immunoprecipitation (IP) and fluorescent co-localization were used to detect the interactions between TRAF6–Beclin1 and Beclin1–PI3KC3, and the ubiquitination of Beclin1. Results: AS inhibited TNF-α and IL-6 release from RAW264.7 cells, mouse bone marrow-derived monocytes (BMDMs) and peritoneal macrophages (PMs) induced by LPS. However, the inhibition by AS of LPS-induced cytokine release decreased when autophagy was inhibited using 3-MA, bafilomycin A1, or a siRNA targeting the Atg5 gene. Notably, AS showed an inhibition of LPS-induced autophagic activation not degradation. Whereas, these effects of AS were lost in macrophages lacking TLR4 and decreased in macrophages with down-regulated TRAF6, indicating that AS inhibited LPS-induced cytokine release and autophagic activation via TLR4-TRAF6 signaling. Western blotting results showed AS could reduce the levels of TRAF6, Beclin1, and PI3KC3. Importantly, the IP results showed AS only inhibited K63-linked ubiquitylation not total ubiquitylation of Beclin1 by acting on TRAF6. This interrupted the TRAF6–Beclin1 interaction and subsequent the formation of Beclin1– PI3KC3 core complex of the PI3K-III complex. Conclusion: AS inhibited LPS-induced cytokine release from macrophages by inhibiting autophagic activation. This effect was tightly related to blockade of the TRAF6-Beclin1-PI3KC3 pathway via decreasing K63-linked ubiquitination of Beclin1 and then interrupting the formation of Beclin1-PI3KC3 core complex of the PI3K-III complex. Our findings reveal the mechanism of AS’s anti-inflammatory effect and is significant for future targeted investigations of sepsis treatment.

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Section: Discussionmentioning

confidence: 99%

Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway

Kuang

Cen

Qin

et al. 2018

Cell Physiol Biochem

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“…The leading cause for admission to an intensive care unit (ICU) is infection and sepsis, accounting for approximately 10 to 45% of ICU stays depending on a variety of health system factors 2, 3 . Despite advances in critical care science, septic shock, as recently defined by the Sepsis-3 task force, carries a mortality rate of 35–54% 4 , with sepsis syndromes resulting in 250,000 deaths annually in the United States alone 5 .…”

Section: Introductionmentioning

confidence: 99%

Delivering Prolonged Intensive Care to a Non-human Primate: A High Fidelity Animal Model of Critical Illness

Poliquin

Biondi

Ranadheera

et al. 2017

Sci Rep

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Critical care needs have been rising in recent decades as populations age and comorbidities increase. Sepsis-related admissions to critical care contribute up to 50% of volume and septic shock carries a 35–54% fatality rate. Improvements in sepsis-related care and mortality would have a significant impact of a resource-intensive area of health care delivery. Unfortunately, research has been hampered by the lack of an animal model that replicates the complex care provided to humans in an intensive care unit (ICU). We developed a protocol to provide full ICU type supportive care to Rhesus macaques. This included mechanical ventilation, continuous sedation, fluid and electrolyte management and vasopressor support in response to Ebolavirus-induced septic shock. The animals accurately recapitulated human responses to a full range of ICU interventions (e.g. fluid resuscitation). This model can overcome current animal model limitations by accurately emulating the complexity of ICU care and thereby provide a platform for testing new interventions in critical care and sepsis without placing patients at risk.

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“…Sepsis is a leading cause of mortality in the intensive care unit of hospitals worldwide [87]. An increasing body of evidence indicates that the IL-33/ST2 axis is involved in the initiation and progression of sepsis [88].…”

Section: Il-33 In Acute Kidney Injurymentioning

confidence: 99%

Emerging Roles of IL-33/ST2 Axis in Renal Diseases

Chen

Yang

2017

IJMS

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Renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), have a great impact on health care systems worldwide. Similar to cardiovascular diseases, renal diseases are inflammatory diseases involving a variety of cytokines. Primary causes of renal injury include ischemia, uremic toxins, bacteremia, or nephrotoxicity. Inflammation represents an important component following kidney injury. Interleukin (IL)-33 is a member of the IL-1 cytokine family, which is widely expressed in epithelial barrier tissues and endothelial cells, and mediates both tissue inflammation and repair responses. IL-33 is released as a nuclear alarmin in response to tissue damage and triggers innate and adaptive immune responses by binding to its receptor, suppression of tumorigenicity 2 (ST2). Recent evidence from clinical and experimental animal studies indicates that the IL-33/ST2 axis is involved in the pathogenesis of CKD, renal graft injury, systemic lupus nephritis, and AKI. In this review, we discuss the pathological and tissue reparative roles of the IL-33/ST2 pathway in different types of renal diseases.

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Sepsis: in search of cure

Abstract: Inability to recognize a single critical mediator of sepsis may be the underlying cause for the poor therapeutic intervention of sepsis. Therefore, sepsis is still considered as a disease-in search of cure.

Cited by 60 publications

References 204 publications

Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway

Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway

Delivering Prolonged Intensive Care to a Non-human Primate: A High Fidelity Animal Model of Critical Illness

Emerging Roles of IL-33/ST2 Axis in Renal Diseases

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