Multiple triggers of cell death in sepsis: death receptor and mitochondrial‐mediated apoptosis

Chang, Katherine; Unsinger, Jacqueline; Davis, Christopher G.; Schwulst, Steven J.; Muenzer, Jared T.; Strasser, Andreas; Hotchkiss, Richard S.

doi:10.1096/fj.06-6805com

Cited by 143 publications

(152 citation statements)

References 59 publications

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“…Animal studies have documented the requirement of an intact T cell system to adequately combat a septic challenge (29,37). More recently, animal-based experiments have demonstrated that experimental septic shock is characterized by widespread T cell apoptosis and that preventing T cell apoptosis positively impacts the outcome of experimental sepsis (38)(39)(40)(41)(42)(43)(44)(45). Importantly, the concept of T cell apoptosis in human sepsis has been indirectly corroborated by autopsy studies (36,46).…”

Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 99%

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Shanley

Cvijanovich²,

Lin

et al. 2007

Mol Med

111

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We have conducted longitudinal studies focused on the expression profiles of signaling pathways and gene networks in children with septic shock. Genome-level expression profiles were generated from whole blood-derived RNA of children with septic shock (n = 30) corresponding to day one and day three of septic shock, respectively. Based on sequential statistical and expression filters, day one and day three of septic shock were characterized by differential regulation of 2,142 and 2,504 gene probes, respectively, relative to controls (n = 15). Venn analysis demonstrated 239 unique genes in the day one dataset, 598 unique genes in the day three dataset, and 1,906 genes common to both datasets. Functional analyses demonstrated timedependent, differential regulation of genes involved in multiple signaling pathways and gene networks primarily related to immunity and inflammation. Notably, multiple and distinct gene networks involving T cell-and MHC antigen-related biology were persistently downregulated on both day one and day three. Further analyses demonstrated large scale, persistent downregulation of genes corresponding to functional annotations related to zinc homeostasis. These data represent the largest reported cohort of patients with septic shock subjected to longitudinal genome-level expression profiling. The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses.

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Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 99%

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Shanley

Cvijanovich²,

Lin

et al. 2007

Mol Med

111

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“…Both the death-receptor and the mitochondrial pathways are likely to be involved in sepsis-induced apoptosis, as well as numerous inducers including steroids, cytokines (TNF-α, HMGB1), Fas ligand, heat shock proteins, oxygen radicals, nitric oxide, and some specific T lymphocytes (13,120,137,138).…”

Section: Monitoring Of Apoptosismentioning

confidence: 99%

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Monneret

Venet

Pachot

et al. 2008

Mol Med

302

323

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“…Mammalian apoptotic cell death in sepsis proceeds through two distinct pathways, the death receptor pathway and the mitochondrial pathway, that converge to activate caspases, resulting in intracellular demolition (25,26). The extrinsic, or death receptor, pathway is triggered by signaling through TNF, Trail and Fas (19,27,28).…”

Section: Discussionmentioning

confidence: 99%

Accelerated apoptosis contributes to aging-related hyperinflammation in endotoxemia

Zhou

Wu²,

Dong³

et al. 2010

Int J Mol Med

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Abstract. Sepsis is associated with an increase in circulating levels of bacterial endotoxin. Sepsis is a particularly serious problem in the geriatric population due to the associated high mortality rate. However, it remains unknown whether this phenomenon is related to an increase in apoptosis in splenic cells. To investigate this issue, male Fischer-344 rats (young, 3 months old; aged, 24 months old) were subjected to endotoxemia by injection of LPS. Splenic samples were collected 4 h thereafter. Apoptosis was determined by cleaved caspase-3 levels and TUNEL staining. The levels of proinflammatory mediators, TNF-·, IL-6 and high mobility group box-1 (HMGB-1), were also measured. Our results showed that, while splenic cell apoptosis increased in the young and aged rats with endotoxemia, the aged animals had much higher levels of apoptotic cell death. The elevated expression of cell cycle inhibitory protein P21 was also observed in the aged animals after treatment with LPS. Moreover, endotoxemia significantly increased TNF-·, IL-6 and HMGB-1. The accelerated apoptosis in the aged animals was correlated with significantly higher levels of TNF-·, IL-6 and HMGB-1. It is suggested that this accelerated rate of apoptosis contributes to age-related hyperinflammation in endotoxemia. To investigate the factors involving accelerated apoptosis in aged animals, we analyzed the Fas/Fas ligand (Fas-L) pathway. Our results showed that Fas and Fas-L gene expression was markedly higher in the spleen in the aged animals after LPS. Similarly, cleaved caspase-8 expression, a downstream element of Fas and Fas-L, was also significantly higher in the aged rats after LPS. Fas-L neutralizing antibodies markedly decreased apoptosis and proinflammatory cytokines in the aged animals after endotoxemia. Thus, there is substantial evidence that the Fas/Fas-L pathway may play an important role in LPS-induced accelerated apoptosis and hyperinflammation in aged animals.

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Multiple triggers of cell death in sepsis: death receptor and mitochondrial‐mediated apoptosis

Cited by 143 publications

References 59 publications

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Accelerated apoptosis contributes to aging-related hyperinflammation in endotoxemia

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