Experimental human endotoxemia as a model of systemic inflammation

Lier, Dirk van; Geven, Christopher; Leijte, Guus P; Pickkers, Peter

doi:10.1016/j.biochi.2018.06.014

Cited by 67 publications

(58 citation statements)

References 54 publications

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“…This interaction leads to an elevation of LPS-TLR4-related proinflammatory cytokines. TNF-α is considered the first mediator that is increased, followed by IL-10 and IL-6 [36,37]. Over 20 years ago, Blazka et al demonstrated a significant increase in serum TNF-α levels after administration of APAP; they also observed that the administration of Kupffer cell inhibitors reduced APAP toxicity in rats [38].…”

Section: Discussionmentioning

confidence: 99%

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats

et al. 2020

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Acetaminophen (APAP) is one of the most used analgesics and antipyretic agents in the world. Intoxication with APAP is the main cause of acute liver toxicity in both the US and Europe. Spore-forming probiotic bacteria have the ability to resist harsh gastric and intestinal conditions. The aim of this study was to investigate the possible protective effect of Bacillus (B) species (sp) spores (B. licheniformis, B. indicus, B. subtilis, B. clausii, B. coagulans) against hepatotoxicity induced by APAP in rats. A total of 35 rats were randomly divided into seven groups: group I served as control; group II received silymarin; group III received MegaSporeBioticTM (MSB); group IV received APAP and served as the model of hepatotoxicity; group V received APAP and silymarin; group VI received APAP and MSB; group VII received APAP, silymarin and MSB. The livers for histopathological examination and blood samples were collected on the last day of the experiment. We determined aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total antioxidant capacity (TAC) levels and zonula occludens (ZO-1), tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) expression. APAP overdose increased AST and ALT. It slowly decreased TAC compared to the control group, but pretreatment with silymarin and MSB increased TAC levels. Elevated plasma concentrations were identified for ZO-1 in groups treated with APAP overdose compared with those without APAP or receiving APAP in combination with silymarin, MSB or both. The changes were positively correlated with the levels of other proinflammatory cytokines (TNF-α, IL-1β). In addition, histopathological hepatic injury was improved by preadministration of MSB or silymarin versus the disease model group. Bacillus sp spores had a protective effect on acute hepatic injury induced by APAP. Pretreatment with MSB resulted in a significant reduction in serum AST, ALT, TNF-α, IL-1β, ZO-1, TAC and also hepatocyte necrosis, similar to the well-known hepatoprotective agent—silymarin.

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Section: Discussionmentioning

confidence: 99%

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats

et al. 2020

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“…To define the circulating miRNA response to endotoxemia without common confounders such as medication and co-morbidities in critically-ill sepsis patients, we employed an experimental low-dose endotoxemia model in combination with P2Y 12 inhibitor treatment in healthy volunteers. Findings were subsequently applied to a cohort of sepsis patients [22].…”

Section: Discussionmentioning

confidence: 99%

“…Next, miRNA profiling was performed in an experimental human model of low-dose endotoxemia [22]. Healthy volunteers from the control group without antiplatelet therapy (n = 6) received an intravenous bolus of 2 ng/kg endotoxin.…”

Section: Effect Of Endotoxemia On Circulating Mirnasmentioning

confidence: 99%

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Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Braza-Boïls

Barwari

Gutmann

et al. 2020

IJMS

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There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y 12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y 12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y 12 inhibition. While P2Y 12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

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“…Endotoxaemia experiments were conducted at the research unit of the intensive care department of the Radboud university medical center according to our standard protocol [8] also used in our previous study into this intervention [1], and an overview of the procedures is depicted in Fig. 2.…”

Section: Procedures On the Endotoxaemia Experiments Daymentioning

confidence: 99%

The combination of cold exposure training and a breathing exercise attenuates the inflammatory response in humans

Zwaag¹,

Naaktgeboren²,

Herwaarden³

et al. 2020

Preprint

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Background - We previously showed that a training intervention encompassing two breathing exercises and exposure to cold enables for voluntary activation of the sympathetic nervous system, reflected by profoundly increased plasma adrenaline levels, and subsequent attenuation of the endotoxin-induced inflammatory response. Herein, we determined the contribution of the different elements of the training, assessed if the training duration is of importance, and whether it can be provided by an independent trainer instead of the well-known individual who devised it. Methods – Forty healthy male volunteers were randomized to either a short or extensive training in both breathing exercises (i.e. cyclic hyperventilation with or without prolonged breath retention) by either the creator of the intervention or an independent trainer. In a subsequent study, 48 healthy male volunteers were randomized to cold exposure training, training in the established optimal breathing exercise, a combination of both, or no training. All 48 subjects were subsequently intravenously challenged with 2 ng/kg lipopolysaccharide to induce endotoxaemia. Results - Both breathing exercises were equally effective in enhancing plasma adrenaline concentrations and this response was also independent from the length of the training or the individual who provided it. Cold exposure training alone did not result in relevant modulation of the endotoxin-induced cytokine response, although flu-like symptoms were markedly reduced compared with the untrained group. Whereas subjects who received training in the breathing exercise alone displayed attenuated plasma levels of pro-inflammatory cytokines IL-6, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1β (-34%, -14%, -48%, -37%, and -28%, respectively) during endotoxemia, combined training resulted in enhanced concentrations of anti-inflammatory IL-10 (+44%) and reduced concentrations of TNF-α, IL-6, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1β (-32%, -35%, -30%, -48%, -29%, -35%, -30%, respectively) compared with untrained individuals. Conclusions - The combination of cold exposure training and a hyperventilation breathing exercise attenuates the in vivo inflammatory response most potently. Our study demonstrates that the immunomodulatory effects of the intervention can be reproduced in a standardized manner, thereby paving the way for clinical trials. Trial registration - Both studies described in this manuscript are registered at www.clinicaltrials.gov (breathing exercises study: NCT02417155; experimental human endotoxaemia study: NCT03240497).

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Experimental human endotoxemia as a model of systemic inflammation

Cited by 67 publications

References 54 publications

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

The combination of cold exposure training and a breathing exercise attenuates the inflammatory response in humans

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