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

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Runkuan Yang ◽  
Xiaoping Zou ◽  
Jyrki Tenhunen ◽  
Tor Inge Tønnessen
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Systemic Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Multiple Organ ◽  
Hepatocyte Regeneration ◽  
Extracellular Histones

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.

scholarly journals Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure

2021 ◽  
Vol 11 ◽  
Author(s):  
Yoram Vodovotz ◽  
Derek Barclay ◽  
Jinling Yin ◽  
Robert H. Squires ◽  
Ruben Zamora
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Systemic Inflammation ◽  
Inflammatory Mediators ◽  
Network Inference ◽  
Inflammatory Responses ◽  
Network Motif ◽  
Dynamic Network ◽  
Central Node ◽  
Pediatric Acute Liver Failure

The Pediatric Acute Liver Failure (PALF) study is a multicenter, observational cohort study of infants and children diagnosed with this complex clinical syndrome. Outcomes in PALF reflect interactions among the child’s clinical condition, response to supportive care, disease severity, potential for recovery, and, if needed, availability of a suitable organ for liver transplantation (LTx). Previously, we used computational analyses of immune/inflammatory mediators that identified three distinct dynamic network patterns of systemic inflammation in PALF associated with spontaneous survivors, non-survivors (NS), and LTx recipients. To date, there are no data exploring age-specific immune/inflammatory responses in PALF. Accordingly, we measured a number of clinical characteristics and PALF-associated systemic inflammatory mediators in daily serum samples collected over the first 7 days following enrollment from five distinct PALF cohorts (all spontaneous survivors without LTx): infants (INF, <1 year), toddlers (TOD, 1–2 years.), young children (YCH, 2–4 years), older children (OCH, 4–13 years) and adolescents (ADO, 13–18 years). Among those groups, we observed significant (P<0.05) differences in ALT, creatinine, Eotaxin, IFN-γ, IL-1RA, IL-1β, IL-2, sIL-2Rα, IL-4, IL-6, IL-12p40, IL-12p70, IL-13, IL-15, MCP-1, MIP-1α, MIP-1β, TNF-α, and NO2−/NO3−. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all sub-groups, with MIG/CXCL9 being a central node in all groups except INF. Dynamic Network Analysis (DyNA) inferred different dynamic patterns and overall dynamic inflammatory network complexity as follows: OCH>INF>TOD>ADO>YCH. Hypothesizing that systemically elevated but sparsely connected inflammatory mediators represent pathological inflammation, we calculated the AuCon score (area under the curve derived from multiple measures over time divided by DyNA connectivity) for each mediator, and identified HMGB1, MIG, IP-10/CXCl10, sIL-2Rα, and MCP-1/CCL2 as potential correlates of PALF pathophysiology, largely in agreement with the results of Partial Least Squares Discriminant Analysis. Since NS were in the INF age group, we compared NS to INF and found greater inflammatory coordination and dynamic network connectivity in NS vs. INF. HMGB1 was the sole central node in both INF and NS, though NS had more downstream nodes. Thus, multiple machine learning approaches were used to gain both basic and potentially translational insights into a complex inflammatory disease.

scholarly journals The Use of Extracorporeal Liver Support Systems In Acute Decompensated Liver Failure

2021 ◽  
Vol 17 (4) ◽  
pp. 12-21
Author(s):  
R. A. Ibadov ◽  
Ye. L. Ismailov ◽  
S. Kh. Ibragimov
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Organ Failure ◽  
Comparison Group ◽  
Support Systems ◽  
Intensive Therapy ◽  
Multiple Organ ◽  
Main Group ◽  
Liver Support ◽  
Extracorporeal Liver Support

The aim of the study: to evaluate the efficacy of extracorporeal liver support systems in patients with acute liver failure of various etiologies.Material and methods. The study included 117 patients with acute liver failure of various etiologies. The main group consisted of 71 patients who received complex intensive therapy, including MARS-therapy and hemodiafiltration. The comparison group included 46 patients who received albumin dialysis (24 patients) and hemodiafiltration (22 patients) alone. The mean age of the patients was 34±5.6 years, the majority (56.4%) were men. Dynamic assessment of patients' severity was performed using Sequential Organ Failure Assessment (SOFA) and Model for End-Stage Liver Disease (MELD) scales.Results. A more significant reduction of SOFA and MELD scores was noted as early as by day 10 of intensive therapy in the main group with sequential use of extracorporeal liver detoxification methods — to 2.7±0.2 vs. 8.3±0.5 points (P=0.021) on SOFA and to 16.7±0.4 vs. 23.4±1.4 points (P=0.023) MELD scales. The use of a comprehensive approach to extracorporeal detoxification in acute decompensated liver failure increased the regression rate of multiple organ failure from 51.2 to 74.6% and reduced mortality from 47.8 to 25.4% (χ2=6.266; df=1; P=0.013). At the same time, the cumulative proportion of survivors depending on the type of complication within 30 days was 88.4% in the main group and 69.0% in the comparison group (χ2=4.164; df=1; P=0.042).Conclusion. A comprehensive approach to extracorporeal detoxification is highly effective, providing a more significant reduction of SOFA and MELD scores, increasing the proportion of regression of multiple organ dysfunction and reducing mortality.

scholarly journals Systemic inflammation downregulates glyoxalase-1 expression: an experimental study in healthy males

2021 ◽  
Author(s):  
Rob GH Driessen ◽  
Dorien Kiers ◽  
Casper Schalkwijk ◽  
Jean LJM Scheijen ◽  
Jelle Gerretsen ◽  
...  
Keyword(s):  
Critical Illness ◽  
Multiple Organ Failure ◽  
Mrna Expression ◽  
Organ Failure ◽  
Systemic Inflammation ◽  
Multiple Organ ◽  
Control Group ◽  
Glyoxalase 1 ◽  
Multi Organ Failure ◽  
Healthy Males

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced downregulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo. Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 hours using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially. Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (p<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (p=0.003). D-lactate was increased in all four groups. L-lactate was increased in all groups, except in the control group. Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.

scholarly journals Angiotensin-(1–7) treatment blocks lipopolysaccharide-induced organ damage, platelet dysfunction, and IL-6 and nitric oxide production in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hsin-Jung Tsai ◽  
Chih-Chin Shih ◽  
Kuang-Yi Chang ◽  
Mei-Hui Liao ◽  
Wen-Jinn Liaw ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Inflammatory Responses ◽  
Multiple Organ ◽  
Biologically Active ◽  
Organ Injury ◽  
Nitric Oxide Production ◽  
Platelet Dysfunction ◽  
Oxide Production

AbstractSepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1–7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1–7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1–7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1–7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1–7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1–7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1–7)-treated LPS rats. Our results suggest that Ang-(1–7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.

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