Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities

Slikke, Elisabeth C. van der; An, Andy Y.; Hancock, Robert E. W.; Bouma, Hjalmar R.

doi:10.1016/j.ebiom.2020.103044

Cited by 62 publications

(49 citation statements)

References 120 publications

(206 reference statements)

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“…The limitation of our study is the unexplored effect of carboplatin in vivo where LPS tolerance is observed such as in sepsis. Sepsis is a systemic inflammatory condition when massive cytokine storms in response to infection is followed by depressed immune response called immune paralysis 39 . Animal models such as two-hit cecal ligation and puncture (CLP), may be used to test whether carboplatin can rescue immune paralysis phenotypes 40 .…”

Section: Discussionmentioning

confidence: 99%

The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

Boonmee

Benjaskulluecha

Kueanjinda

et al. 2021

Sci Rep

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Following re-exposure to lipopolysaccharide (LPS), macrophages exhibit an immunosuppressive state known as LPS tolerance, which is characterized by repressed proinflammatory cytokine production. LPS-induced tolerance in macrophages is mediated in part by epigenetic changes. Carboplatin, an anticancer chemotherapeutic drug, exerts its effect by inhibiting DNA replication and transcription, as well as through epigenetic modifications. Through an unbiased screen, we found that carboplatin rescued TNF-α and IL-6 production in LPS-tolerant macrophages. Transcriptomic analysis and gene set enrichment analyses revealed that p53 was one of the most significantly upregulated hallmarks in both LPS-primed and LPS-tolerant macrophages in the presence of carboplatin, while E2F and G2/M were the most negatively regulated hallmarks. Heterochromatin protein 1 (HP1-α), which is associated with gene silencing, was significantly reduced in carboplatin-treated LPS-tolerant macrophages at the mRNA and protein levels. Dynamic changes in the mRNA level of genes encoding H3K9me3 methyltransferases, setdb2, kdm4d, and suv39h1 were induced in the presence of carboplatin in LPS-tolerant macrophages. Taken together, we provide evidence that carboplatin treatment interferes with proinflammatory cytokine production during the acute LPS response and LPS tolerance in macrophages, possibly via H3K9me3 modification.

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Section: Discussionmentioning

confidence: 99%

The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

Boonmee

Benjaskulluecha

Kueanjinda

et al. 2021

Sci Rep

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“…However, in high-income countries the long-term survival is improving, with approximately 14 million sepsis survivors each year [ 8 ], raising at the same time new health consequences and a significant burden for patients and society [ 9 , 10 ]. Thus, post-sepsis syndrome involves multiple long-term deficits, including the immune, cognitive, psychiatric, renal, and cardiovascular systems [ 11 , 12 ]. Notably, nearly a quarter of sepsis survivors will be readmitted to hospital within 30 days of discharge [ 13 ].…”

Section: Sepsis As a Global Health Prioritymentioning

confidence: 99%

Long-term cardiovascular complications following sepsis: is senescence the missing link?

Merdji

Schini‐Kerth

Meziani

et al. 2021

Ann. Intensive Care

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Among the long-term consequences of sepsis (also termed “post-sepsis syndrome”) the increased risk of unexplained cardiovascular complications, such as myocardial infarction, acute heart failure or stroke, is one of the emerging specific health concerns. The vascular accelerated ageing also named premature senescence is a potential mechanism contributing to atherothrombosis, consequently leading to cardiovascular events. Indeed, vascular senescence-associated major adverse cardiovascular events (MACE) are a potential feature in sepsis survivors and of the elderly at cardiovascular risk. In these patients, accelerated vascular senescence could be one of the potential facilitating mechanisms. This review will focus on premature senescence in sepsis regardless of age. It will highlight and refine the potential relationships between sepsis and accelerated vascular senescence. In particular, key cellular mechanisms contributing to cardiovascular events in post-sepsis syndrome will be highlighted, and potential therapeutic strategies to reduce the cardiovascular risk will be further discussed.

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“…Such effects were correlated with diminishing the systemic IFN-γ synthesis, decrease of microbicidal activities of their neutrophils, phagocytosis and NO production [124]. Cardiac dysfunction is a well-known serious complication of sepsis [125]. A recent study suggested that IL-12p35 [Il12a] may be considered an important target during the management of such complications as its deletion worsened CLP-induced cardiac dysfunction [126].…”

Section: Interleukin-12mentioning

confidence: 99%

Cytokines in sepsis: friend or enemy?

Senousy

Ahmed

El‐Daly

et al. 2021

Journal of advanced Biomedical and Pharmaceutical Sciences

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Infectious diseases are a major cause of death worldwide. A serious complication of infections is septic shock. Septic shock is a critical syndrome associated with the host response to infection. The severity of infections is related to an activation cascade that results in a magnification of the cytokine production which is termed "cytokine storm". Despite the commonly elucidated etiology of sepsis and its clinical course, the actual progress in therapeutic strategies is still limited. Several studies were carried out on the pathophysiology of sepsis-induced imbalance in the inflammatory/anti-inflammatory response as the main cause of tissue damage, organ failure, and eventually, death. Cytokines are crucial pleiotropic regulators of the immune response, which have an important role in the complicated pathophysiology of sepsis. They possess both pro-and anti-inflammatory properties and are capable of exerting efficacious defense responses towards invading pathogens. On the other hand, cytokines may disturb the immune response and reinforce inflammation. Thus, achieving a balance between these two effects will improve the prognosis of sepsis. Blocking the activities of pro-inflammatory cytokines promotes survival in animal models of sepsis, yet, such a treatment strategy did not enhance the clinical outcome. In this review, we will describe the mechanisms underlying the pathogenesis of the cytokine storm during sepsis and represent in detail the role of cytokines responsible for cell or organ damage. We will compare the various therapeutic approaches investigated to stop or suppress this mischievous process and discuss the reasons for therapeutic failure.

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Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities

Cited by 62 publications

References 120 publications

The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

Long-term cardiovascular complications following sepsis: is senescence the missing link?

Cytokines in sepsis: friend or enemy?

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