interleukin-8 and Liver-Failure--Acute

The effectiveness of plasma exchange (PE) with continuous hemodiafiltration (CHDF) in the treatment of critically ill patients was evaluated based on changes in cytokine levels. Twenty-six patients with acute hepatic failure were treated with PE (PE group) or PE and CHDF (PE+CHDF group), and the levels of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were determined before and after treatment. Bilirubin levels were significantly lower after treatment in both the PE and PE+CHDF groups. There were no significant differences in TNF-alpha levels before and after treatment in the PE group, but the TNF-alpha level was significantly lower after treatment in the PE+CHDF group. There were no significant differences in the IL-6 levels before and after treatment in both the PE and PE+CHDF groups. There were no significant differences in IL-8 levels before and after treatment in the PE group, but the IL-8 level was significantly lower after treatment in the PE+CHDF group. PE with CHDF therapy was given to 5 patients with acutely aggravated autoimmune diseases, 2 patients with hemorrhagic shock and encephalopathy syndrome, and 3 patients with thrombotic microangiopathy. The results suggested that PE with CHDF therapy are useful in critically ill patients with suspected hypercytokinemia.

Topics: Adult; Aged; Autoimmune Diseases; Bilirubin; Blood Coagulation Disorders; Critical Illness; Cytokines; Female; Hemodiafiltration; Humans; Interleukin-6; Interleukin-8; Liver Failure, Acute; Male; Middle Aged; Plasma Exchange; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

We studied citric acid levels and proinflammatory cytokines (TNF-alpha, IL-6, and IL-8) before and after plasma exchange in 8 patients with acute liver failure. Plasma exchange was performed over a 6 to 7-hour period. At each session, 3.6 to 4.0 1 of plasma was exchanged for the same volume of fresh frozen plasma (FFP). The concentrations of citric acid were significantly increased after plasma exchange above concentrations before exchange (p<0.0001). There were no significant differences in TNF-alpha, IL-6, or IL-8 concentrations (p=0.7222, p=0.9357, p=0.6394, respectively). Thus, plasma exchange with FFP alone may not effectively remove cytokines.

Topics: Adult; Aged; Citric Acid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Liver Failure, Acute; Male; Middle Aged; Plasma Exchange; Tumor Necrosis Factor-alpha

The prognosis of acute liver failure (ALF) remains poor, and liver transplantation is an alternative treatment option. Assessing the prognosis of ALF is important in determining treatment strategies. Here, we investigated clinical factors including serum pro-inflammatory cytokine levels that are associated with the prognosis of ALF.. Sixty-six patients who developed ALF were enrolled in this study. Serum concentrations of 12 pro-inflammatory cytokines were measured on admission. The prognosis and factors associated with survival and development of hepatic coma were analyzed.. Of 66 patients, 4 patients underwent liver transplantation, and 49 patients were rescued without liver transplantation, while the remaining 13 patients died. Serum concentrations of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-13, TNF, IFN -γ, IP-10, and G-CSF were significantly elevated in ALF patients. IL-4 and IL-8 levels were higher in patients who underwent liver transplantation or died than in rescued patients. Multivariable analysis identified age ≥ 55 years and IL-4 ≥ 1.2 pg/mL on admission as independent factors for mortality. Serum IL-8 levels were higher in patients with hepatic coma, and prothrombin-international normalized ratio ≥ 3.5 and IL-8 ≥ 77.2 pg/mL on admission were associated with development of hepatic coma after admission.. Serum levels of several pro-inflammatory cytokines were elevated in ALF patients. IL-4 and IL-8 were correlated with survival and development of hepatic coma after admission, respectively. Measurement of serum pro-inflammatory cytokines seems to be useful for the management of ALF.

Topics: Cytokines; Hepatic Encephalopathy; Humans; Interleukin-4; Interleukin-8; Liver Failure, Acute; Middle Aged; Prognosis

Ex vivo perfused porcine livers have been used for temporary support during acute liver failure. The aim of this study was to assess both the histological changes and temporal pattern of the changes that occur during extracorporeal liver perfusions and to correlate these with factors that may influence them. Five porcine livers were harvested, preserved in cold ice and reperfused for 6 h in an extracorporeal circuit using autologous normothermic blood. Tissue biopsies were collected hourly. The Ishak score was used to quantify hepatic necrosis, and immunohistochemistry was used to evaluate apoptosis and regeneration. Liver weight, perfusion parameters, arterial blood gases and blood samples were also collected. The Ishak score peaked immediately before and 4 h after the start of reperfusion. Scattered necrosis, microvesicular steatotic vacuolization, sinusoidal dilatation and red cell extravasation were present. Anion gap acidosis was associated with the Ishak score. An inverse correlation was present between liver regeneration and necrosis, and between liver weight and regeneration. No changes were observed for apoptosis. Among the inflammatory cytokines evaluated, interleukin-6 and -8 levels increased significantly during the perfusions. Hepatic necrosis was always present during the extracorporeal perfusions, followed a definite pattern and was inversely correlated with regeneration. Apoptosis did not increase over baseline levels. The meaning of these findings and their correlation with clinical outcomes during acute hepatic failures deserve further investigation.

Topics: Animals; Biopsy; Cold Ischemia; Extracorporeal Circulation; Female; Immunohistochemistry; Interleukin-6; Interleukin-8; Liver; Liver Failure, Acute; Liver Function Tests; Logistic Models; Organ Size; Perfusion; Statistics, Nonparametric; Swine; Transducers; Warm Ischemia

Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls.. In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bone Marrow Cells; Chemical and Drug Induced Liver Injury; Chemokine CCL2; Chemokine CCL3; Chemotaxis; Female; Humans; Interleukin-10; Interleukin-8; Ki-67 Antigen; Liver Failure, Acute; Macrophages; Male; Middle Aged; Monocytes; Receptors, CCR2; Transforming Growth Factor beta1

Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9(-/-) mice).. Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.

Topics: Acetaminophen; Acute Lung Injury; Acute-Phase Reaction; Adolescent; Adult; Analysis of Variance; Animals; Cell Movement; Chemokines; Child; Coculture Techniques; DNA, Mitochondrial; Female; Hep G2 Cells; Humans; Interleukin-8; Liver; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mitochondrial Proteins; Necrosis; Neutrophils; Receptors, Formyl Peptide; Receptors, Interleukin-8B; Signal Transduction; Systemic Inflammatory Response Syndrome; Toll-Like Receptor 9; Young Adult

High-mobility group box-1 (HMGB1) plays important roles in inflammation, immune responses, and tumor progression. Since HMGB1 and its components have been shown to be mediators of a number of diseases but several sources of recombinant HMGB1 showed controversial biological activity, it is important to obtain recombinant HMGB1 with properties that resemble the native protein. For this purpose, we cloned genes coding for human HMGB1 and its active components A box and B box by PCR and inserted the cloned genes into pET28a vectors for transformation of Escherichia coli BL21. The E. coli expressed proteins were then purified with a Ni(2+)-NTA column and the endotoxin content was removed. Recombinant human HMGB1 (rhHMGB1) and its B box thus obtained stimulated, but A box inhibited, the production of the chemokine CXCL8/IL-8 by THP-1 monocytic cell line. We also used purified rhHMGB1 to immunize rabbits and generated potent anti-sera, which was capable of neutralizing the activity of rhHMGB1 in vitro and detecting the increased HMGB1 expression in inflammatory tissues in mice and humans. Thus, we have established essential means to produce biologically active rhHMGB1 that will facilitate us to study its role in diseases and to explore its potential as a therapeutic agent.

Topics: Animals; Cell Line; Cloning, Molecular; Concanavalin A; Escherichia coli; HMGB1 Protein; Humans; Immune Sera; Immunization; Inflammation; Interleukin-8; Liver Failure, Acute; Mice; Monocytes; Psoriasis; Rabbits; Recombinant Proteins; Transformation, Bacterial

Damage to endothelial cells may be an important factor in the complications of acute liver failure, resulting in multi-organ failure. The aim of this study was to assess endothelial cell function in patients with severe hepatotoxicity due to paracetamol ingestion.. Fifty-eight patients with paracetamol-induced hepatotoxicity were studied for up to 7 days. Serum hyaluronic acid (HA), as a marker of hepatic sinusoidal endothelial cell function, was determined using an enzyme-linked binding assay. Plasma von Willebrand Factor, thrombomodulin and interleukin-8 were also determined using ELISA.. Serum HA on admission was significantly increased (median 6777 ng/ml, range 24-50 967 ng/ml) as compared to normal controls (n = 10, median 21 ng/ml, range 0-50 ng/ml; P < 0.001). In non-survivors (n = 21) HA levels peaked on day 2 after admission (P = 0.044), and then decreased. In the survivors (n = 37) the levels of HA did not increase further. Plasma von Willebrand Factor, plasma thrombomodulin and serum interleukin-8 were significantly increased in the patients as compared to the normal controls (P < 0.001). Serum interleukin-8 was significantly higher in non-survivors in the first 2 days.. Endothelial function is abnormal in paracetamol-induced hepatotoxicity. Damage to hepatic sinusoidal endothelial cells assessed by serum HA was greater in non-survivors than survivors.

Topics: Acetaminophen; Adolescent; Adult; Aged; Analgesics, Non-Narcotic; Biomarkers; Endothelium, Vascular; Female; Humans; Hyaluronic Acid; Interleukin-8; Liver Failure, Acute; Liver Transplantation; London; Male; Middle Aged; Patient Admission; Statistics as Topic; Survival Analysis; Thrombomodulin; Time Factors; Treatment Outcome; Ultrafiltration; von Willebrand Factor

To evaluate the effectiveness and mechanisms of molecular adsorbents recirculating system (MARS) treatment in severe liver failure patients with multiple organ dysfunction syndrome (MODS).. 60 single MARS treatments were performed for 6 - 24 hours on 24 severe liver failure patients with MODS.. MARS therapy was associated with marked reduction of albumin bound toxins and water soluble toxins, together with a significant removal of NO and certain cytokines, such as TNF-alpha, IL-6, IL-8, and INF-gamma. These were associated with a improvement of the patients' clinical conditions including hepatic encephalopathy, deranged hemodynamic situation, as well as renal and respiratory function, thus resulted into marked decrease of sequential organ failure assessment (SOFA) score (from 9.72+-1.89 to 6.98+-2.34), and improving outcome: 9 patients were able to be discharged from the hospital or bridged to successful liver transplantation. The overall survival rate of 24 patients was 37.5%.. There is positive therapeutic impact and safety to use MARS on liver failure patients with MODS. The effectiveness of MARS is correlated with reducing the levels of NO and cytokines, except for completely removing of accumulated toxins in liver failure patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bioreactors; Female; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Liver Failure, Acute; Liver, Artificial; Male; Middle Aged; Multiple Organ Failure; Nitric Oxide; Sorption Detoxification; Tumor Necrosis Factor-alpha

Molecular Adsorbents Recirculating System (MARS) is a new promising artificial liver support therapy, the aim of this study was to assess the effectiveness of MARS to remove nitrous oxide (NO) and cytokines in severe liver failure patients with multiple organ dysfunction syndrome (MODS).. Sixty single MARS treatments were performed with length of 6-24 h on 24 severe liver failure patients (18 males/6 females) with MODS.. The MARS therapy was associated with a significant removal of NO and certain cytokines such as TNF-alpha, IL-6, IL-8, and INF-gamma, together with marked reduction of other non-water-soluble albumin bound toxins and water-soluble toxins, these were associated with a improvement of the patients' clinical conditions including hepatic encephalopathy, deranged hemodynamic situation and as well as renal and respiratory function, thus resulted into marked decrease of Sequential Organ Failure Assessment (SOFA) score and improved outcome: nine patients were able to be discharged from the hospital or bridged to successful liver transplantation, the overall survival of 24 patients was 37.5%.. We can confirm the positive therapeutic impact and safety to use MARS on liver failure patients with MODS associated with elevated levels of NO and cytokines.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cytokines; Female; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Liver Failure, Acute; Male; Middle Aged; Multiple Organ Failure; Nitrous Oxide; Renal Dialysis; Severity of Illness Index; Sorption Detoxification; Toxins, Biological; Tumor Necrosis Factor-alpha

Plasma exchange has gained widespread acceptance as an effective mode of blood purification in patients suffering from acute hepatic failure. However, it is still undetermined whether a single use of plasma exchange is capable of removing inflammatory cytokines completely or of preventing the development of citrate toxicity inherent with fresh frozen plasma. To clarify these issues we developed combined plasma exchange and continuous hemodiafiltration (CHDF) modality in which CHDF is performed in an opposite direction to plasma exchange. This study was designed to assess the effectiveness of combined modality therapy. Fifteen patients with acute hepatic failure were treated with plasma exchange (plasma exchange group) or plasma exchange and CHDF (plasma exchange + CHDF group), and various biochemical parameters were determined before and after treatment. Although citrate levels increased significantly after treatment compared with pretreatment levels in both the plasma exchange group and the plasma exchange + CHDF group, the percentage of the increase in citrate levels was significantly higher in the plasma exchange group than in the plasma exchange + CHDF group. Bilirubin levels were significantly lower after treatment in both the plasma exchange and plasma exchange + CHDF groups. There were no significant differences in tumor necrosis factor-alpha levels before and after treatment in the plasma exchange group, but they were significantly lower after treatment in the plasma exchange + CHDF group. Interleukin-6 (IL-6) levels increased significantly after treatment in the plasma exchange group, but there were no significant differences in the IL-6 levels before and after treatment in the plasma exchange + CHDF group. Interleukin-8 levels increased significantly after treatment in the plasma exchange group while decreasing significantly after treatment in the plasma exchange + CHDF group. These results indicate that combining plasma exchange and CHDF in a parallel circuit is an effective modality for suppressing the elevation of blood citrate levels and for removing inflammatory cytokines. This finding may have important implications for the development of an effective treatment for patients with acute hepatic failure.

Topics: Citrates; Combined Modality Therapy; Female; Hemodiafiltration; Humans; Interleukin-6; Interleukin-8; Liver Failure, Acute; Male; Middle Aged; Plasma Exchange; Treatment Outcome; Tumor Necrosis Factor-alpha