Are alterations of lymphocyte subpopulations in polymicrobial sepsis and DHEA treatment mediated by the tumour necrosis factor (TNF)-<i>α</i>receptor (TNF-RI)? A study in TNF-RI (TNF-RI–/–) knock-out rodents

Hildebrand, Frank; Pape, Hans-Christian; Harwood, Paul; Wittwer, T.; Krettek, Christian; Griensven, Martijn van

doi:10.1111/j.1365-2249.2004.02598.x

Cited by 14 publications

(10 citation statements)

References 49 publications

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“…Accordingly, DHEA restored the depressed splenocyte proliferative activity, decreased splenocyte apoptosis rate, and increased the number of circulating NK-cells and CD8+-lymphocytes in septic rats [104][105][106]109]. It was further reported that DHEA decreased plasma IL-10, IL-6, and TNFconcentrations and this was interpreted as a DHEA-induced attenuation of the systemic inflammatory response during sepsis [110].…”

Section: Dhea In Critical Illnessmentioning

confidence: 85%

Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects. Is there Any Possible Option in the Treatment of Critical illness?

Oberbeck¹,

Kobbe

2010

CMC

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DHEA is the major circulating steroid in human blood and it is a central intermediate in the metabolic pathway of sex steroid hormone formation. Although the specific effect of DHEA is still unclear it was demonstrated that DHEA modulates several physiologic processes including metabolism and cardiovascular function. Furthermore, a profound immunomodulatory effect of DHEA was reported. Several data demonstrate the beneficial effect of DHEA in situations of critical illness including trauma hemorrhage and sepsis. Accordingly DHEA improved the survival rate and clinical situation in several animal models of trauma hemorrhage and systemic inflammation. This effect was paralleled by profound changes of immunologic parameters, organ function, and heat shock protein production. Therefore, it was claimed that DHEA may be a new alternative/additive in the treatment of trauma and sepsis. In line, DHEA is a frequently used drug in the field of anti-aging medicine, it is an over-the-counter drug in several countries, and it was reported that DHEA medication is free of major side effects. Therefore, DHEA could easily be used in a clinical trial investigating its effects in critical ill patients. This article reviews the reported effects of DHEA on the base of the literature with the specific focus on trauma and sepsis/critical illness including its clinical perspectives.

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Section: Dhea In Critical Illnessmentioning

confidence: 85%

Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects. Is there Any Possible Option in the Treatment of Critical illness?

Oberbeck¹,

Kobbe

2010

CMC

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“…DHEA administration in systemic lupus erythematosus has significantly reduced disease activity and glucocorticoid dose requirements (34 -36). Of note, in rodent models of experimental sepsis, DHEA has consistently exerted beneficial effects (15)(16)(17)(18)(19)(20)(21). However, these results need to be interpreted with caution because the rodent does not produce DHEA from the adrenal; circulating concentrations of DHEA and DHEAS are of gonadal origin and are very low.…”

Section: Discussionmentioning

confidence: 99%

“…Such a shift may have a negative impact on the immune response to stress by disrupting the balance between cortisoland DHEA-induced immune effects (13). Furthermore, DHEA administration has beneficial effects on experimentalinduced sepsis in rodents (15)(16)(17)(18)(19)(20)(21). On this basis, DHEA deficiency in septic shock in man may warrant DHEA replacement therapy (12,22,23).…”

mentioning

confidence: 99%

Dissociation of Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Septic Shock

Arlt¹,

Hammer²,

Sanning

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

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Context: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels.Objective: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality.Design, Setting, and Participants: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls.Main Outcome Measures: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation.Results: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P Ͻ 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P Ͻ 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P ϭ 0.069) and lower DHEA (P ϭ 0.076) and a significantly higher cortisol to DHEA ratio (P ϭ 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P ϭ 0.026), whereas survivors did not differ from controls (P ϭ 0.322). Conclusions:The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid-and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.

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“…Taking into account that TNF-α is implicated in the pathophysiology of several CNS diseases, we studied the neurological outcome of sepsis in TNF receptor type 1 (TNFR1) knockout (KO) mice. We hypothesized that TNFR1 KO mice would have long-term cognitive impairment, and this would be associated with elevated expression of inflammatory cytokines in the brain after sepsis as previously described in these KO mice (Hildebrand et al 2004). As BDNF is involved in brain functioning, including learning and memory, we also evaluated the brain expression of BDNF and its receptor TrKb.…”

Section: Introductionmentioning

confidence: 92%

TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

et al. 2014

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The involvement of TNF-α type 1 receptor (TNFR1) in memory deficits induced by sepsis was explored by using TNFR1 knockout (KO) mice. We reported that wild type (WT) mice presented memory deficits in the novel object recognition test 10 days after sepsis induced by cecum ligation and perforation (CLP). These deficits were not observed in TNFR1 KO mice. The involvement of serum and brain cytokines TNF-α, IL-1β, IL-6, IFN-γ and IL-10 was then investigated. TNFR1 KO mice had higher serum levels of TNF-α and IL-1β, and brain levels of TNF-α than WT mice. After CLP, the brain levels of TNF-α, IL-1β, IL-6 and IFN-γ increased in both WT and KO mice. Our next step was to determine the expression of inflammatory cytokines, BDNF and TrKb in the hippocampus. The absence of TNFR1 in mice subjected to polymicrobial sepsis resulted in higher BDNF expression in the hippocampus. In conclusion, after CLP, memory is preserved in the absence of TNFR1. This finding was associated with increased BDNF expression in the hippocampus.

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Are alterations of lymphocyte subpopulations in polymicrobial sepsis and DHEA treatment mediated by the tumour necrosis factor (TNF)-αreceptor (TNF-RI)? A study in TNF-RI (TNF-RI–/–) knock-out rodents

Cited by 14 publications

References 49 publications

Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects. Is there Any Possible Option in the Treatment of Critical illness?

Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects. Is there Any Possible Option in the Treatment of Critical illness?

Dissociation of Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Septic Shock

TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

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