Dataset Information

HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

ABSTRACT: Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT). BT triggers/induces systemic inflammatory responses syndrome (SIRS), which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

SUBMITTER: Yang R

PROVIDER: S-EPMC5485317 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

Yang Runkuan R Zou Xiaoping X Tenhunen Jyrki J Tønnessen Tor Inge TI

Mediators of inflammation 20170613

Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bact ...[more]

PMID: 28694564

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Project description:AimHigh mobility group box (HMGB)-1 has been implicated in endometriosis due to the important regulatory roles of inflammation in endometriosis. The aim of the present study was to explore the roles of HMGB-1 in endometriosis and to elucidate the underlying mechanism.MethodsEndometrial specimens were collected from women with endometriosis and healthy volunteers. Immunohistochemistry staining was used to determine the expression patterns and localization of HMGB-1 in the normal, eutopic and ectopic endometrial tissues. Western blotting and qRT-PCR were used to determine the mRNA and protein levels of inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β], autophagy-related markers [beclin-1, autophagy-related (atg)13, microtubule-associated protein light chain (LC)3-I, LC-II and p62] and HMGB-1, respectively. Spearman's rank correlation analysis was employed to investigate the correlation between HMGB-1 with inflammatory cytokines and beclin-1. Besides, human endometrial stromal cells (HESCs) were isolated from ectopic endometrium and subsequently transfected with shRNA against HMGB-1. After the transfected cells were subjected to hypoxia, ELISA was used to determine the levels of HMGB-1 and inflammatory cytokines in the cell supernatant. Western blotting was used to determine the expression levels of autophagy-related markers in the cells.ResultsPositive correlations were observed between HMGB-1 and the inflammatory cytokines. In addition, a positive correlation was also identified between HMGB-1 and beclin-1 in the ectopic endometrium. Further results demonstrated that autophagy-related markers beclin-1, atg13 and p62 were significantly upregulated in the ectopic endometrium. In addition, HMGB-1 knockdown suppressed the levels of inflammatory cytokines IL-6, TNF-α and IL-1β and autophagy-related markers beclin-1 and atg13, while upregulated p62 in HESCs under hypoxic condition.ConclusionKnockdown of HMGB-1 under hypoxic condition regulated inflammatory cytokines and autophagy-related markers. HMGB-1 might contribute to the development of endometriosis in part through regulating inflammatory response and autophagy.

Project description:BackgroundTo explore the effects of extracellular histones released by activated neutrophils on systemic-onset juvenile idiopathic arthritis (SoJIA), and to study the change of serum histone level between the active and remissive stage of SoJIA, then to clarify the role of serum histone in the pathogenesis of SoJIA.MethodsTwenty-six patients with SoJIA were recruited, and clinical informations were collected, and the serum histone was detected by ELISA. While neutrophils from normal children were incubated with the serum from the patients with SoJIA, also including incubated with FeCL3 and histone, the extracellular histone was detected, respectively; heparin was added to the above-mentioned groups to observe the changes of extracellular histone levels. The proportions of neutrophils, which released NETs, were calculated by confocal microscope.ResultsThe levels of serum histones in active SoJIA group (0.90 ± 0.90) were significantly higher than in remissive SoJIA group (0.17 ± 0.10) (P = 0.0009), and also higher than in control group (0.14 ± 0.09) (P = 0.246). Histone affects on clinical manifestations (including fever, rash, joint pain, liver and spleen enlargement, and serositis), except for joint pain. The proportions of neutrophils releasing NETs, that neutrophils were incubated with the serum from active SoJIA group, were 31.93% significantly higher than 12.32% from remissive SoJIA group (P < 0.0001). The proportions of neutrophils releasing NETs, that neutrophils were incubated with different concentration FeCl3 or with different concentration histones respectively, were positively correlated with the concentration of incubation; while heparins were added, NETs from neutrophils could be reduced effectively.ConclusionsThe level of serum histone is positively correlated with the activity of SoJIA. Serum histone may be from NETs, which were released by activated neutrophils. Free iron can activate neutrophils to produce NETs, which may release histones, and histones can further promote NETs to be released, that results in a positive feedback loop of histones, and that may be one of the pathogenesis of acute SoJIA or MAS secondary to SoJIA. Histones maybe play one of important roles in the pathogenesis of SoJIA. Heparin can act on histones to prevent histone-induced inflammation.Trial registrationChiCTR-OOC-15006228. Registered 9 April 2015, http://www.chictr.org.cn/showproj.aspx?proj=10752.

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Project description:Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.

Dataset Information

HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

Publications

HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

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