Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

Weiss, Scott L.; Cvijanovich, Natalie Z.; Allen, Geoffrey L.; Thomas, Neal J.; Freishtat, Robert J.; Anas, Nick; Meyer, Keith; Checchia, Paul A.; Shanley, Thomas P.; Bigham, Michael T.; Fitzgerald, Julie C.; Banschbach, Sharon; Beckman, Eileen; Howard, Kelli; Frank, Erin; Harmon, Kelli; Wong, Hector R.

doi:10.1186/preaccept-2292040841290621

Cited by 10 publications

(15 citation statements)

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“…Acute mitochondrial dysfunction may contribute to MOF. Reduced mitochondrial oxygen utilisation and gene expression has been observed in established sepsis in adults and children [ 3 ]. There is an association between recovery of mitochondrial function and survival but the contribution to the onset of organ failure is less clear.…”

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confidence: 99%

Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

et al. 2015

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confidence: 99%

Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

et al. 2015

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“…We first determined how many gene probes were differentially regulated between children with septic shock (n =180) and healthy control pediatric subjects (n =53). The demographic characteristics of the two study groups were reported previously by Weiss et al [ 16 ]. We conducted a Welch’s t test starting with all 54,675 gene probes on the array and corrected for multiple comparisons using a Benjamini-Hochberg FDR of 5 %.…”

Section: Resultsmentioning

confidence: 99%

“…We next determined whether the Nrf2-linked genes were differentially regulated across previously validated gene expression-based subclasses of pediatric septic shock: endotype A and endotype B [ 29 ]. The clinical and demographic data for the patients in septic shock endotype A (n =60) and endotype B (n =160) have been previously published by Weiss et al [ 16 ]. Patients with endotype A have a higher mortality rate, Pediatric Risk of Mortality score, and pediatric sepsis biomarker risk model–based mortality risk, as well as the maximum number of organ failures, compared with patients in endotype B.…”

Section: Resultsmentioning

confidence: 99%

“…Evidence for mitochondrial dysfunction in pediatric septic shock is supported by a recent report that nuclear-encoded mitochondrial genes are differentially expressed early in pediatric septic shock compared with healthy controls and across septic shock endotypes [ 16 ]. Moreover, direct measurements of mitochondrial respiration demonstrated decreased bioenergetic reserve and increased mitochondrial uncoupling in peripheral blood mononuclear cells of children with early sepsis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of the Nrf2-linked genes in pediatric septic shock

et al. 2015

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IntroductionExperimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.MethodsWe conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated from whole blood within 24 h of pediatric intensive care unit admission for septic shock and a false discovery rate of 5 %. We compared differentially expressed genes from (1) patients with septic shock and healthy controls and (2) across validated gene expression–based subclasses of pediatric septic shock (endotypes A and B) using several bioinformatic methods.ResultsWe found upregulation of 123 Nrf2-linked genes in children with septic shock. The top gene network represented by these genes contained primarily enzymes with oxidoreductase activity involved in cellular lipid metabolism that were highly connected to the peroxisome proliferator activated receptor and the retinoic acid receptor families. Endotype A, which had higher organ failure burden and mortality, exhibited a greater downregulation of Nrf2-linked genes than endotype B, with 92 genes differentially regulated between endotypes.ConclusionsOur findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1052-0) contains supplementary material, which is available to authorized users.

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“…In animal models of sepsis and trauma, mitochondrial abnormalities have been reported across vital organ systems (93,94). In humans, decreased mitochondrial oxygen consumption, low ATP, and mitochondrial gene repression have been linked to illness severity and death (95–98). Metabolomic studies further suggest that energetic substrates related to fatty acid oxidation and the citric acid cycle are less efficiently utilized through mitochondrial aerobic respiration in sepsis non-survivors than in survivors (99).…”

Section: Pamps and Dampsmentioning

confidence: 99%

Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome

Carcillo

Podd

Aneja

et al. 2017

Pediatric Critical Care Medicine

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Objective To describe the pathophysiology associated with multiple organ dysfunction syndrome (MODS) in children. Data Sources Literature review, research data, and expert opinion Study Selection Not applicable Data Extraction Moderated by an experienced expert from the field, pathophysiological processes associated with MODS in children were described, discussed and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for MODS. Children with MODS have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation, 2) increased circulating damage associated molecular pattern molecules (DAMPS) from injured tissues, 3) increased circulating pathogen associated molecular pattern molecules (PAMPS) from infection or endogenous microbiome, and 4) cytokine driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas DAMPS and PAMPS alone and together amplify the cytokine production leading to the inflammatory MODS response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of MODS pathobiology phenotypes. Thrombocytopenia associated MODS patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and ADAMTS13. Sequential MODS patients have sfasL-fas mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immune paralysis associated MODS patients have impaired ability to resolve infection, and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of MODS requires elimination of the source of inflammation. Full recovery of organ functions is noted six to eighteen weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.

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Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

Cited by 10 publications

References 56 publications

Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

Differential expression of the Nrf2-linked genes in pediatric septic shock

Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome

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