Printer Friendly

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

1. Background

Acute liver failure is defined as a clinical syndrome characterized by liver injury with evidence of coagulopathy and any degree of altered mental status in a patient without preexisting liver disease and duration of illness less than 26 weeks [1-3]. The etiology varies with geography. Hepatotrophic viruses are the most common cause of ALF in developing countries [4, 5]; drugs are the most common cause of ALF in the industrialized nations [4, 6]. The mortality of ALF is as high as 40-50%, and the cause of death in ALF includes brain herniation due to raised intracranial pressure (35%) and sepsis with multiple organ failure [3]. Liver transplantation is the only therapeutic intervention with proven survival benefit in patients with irreversible ALF [2]. ALF patients are prone to infection due to the immunologic defect and the high-dependency care they require [7]. Between 39% and 57% of ALF patients experience bacterial infection [8]. ALF has a high rate of infection with gram-negative enteric bacteria in animal model [9]. Gram-negative and gram-positive bacteria can elicit sepsis [7]. Infections and/or the resulting SIRS are important contributing factors that worsen hepatic encephalopathy (HE) [8]. ALF is associated with MOF and a high incidence of sepsis (35.7%), which contributes to 23.1% of the mortality [7]; however, the underlying mechanism is still not clear. Early inflammatory mediators (such as TNF-[alpha], and IL-1[beta] certainly involved in the pathogenesis of ALF [10]; however, these early cytokines have limited clinical significance due to the narrow therapeutic window. In contrast, HMGB1 is a late mediator of lethal systemic inflammation [11], and HMGB1 has a prolonged therapeutic window as compared to those early inflammatory cytokines; circulating TNF-[alpha] and IL-6 are elevated for 5 days after the onset of sepsis, and serum HMGB1 levels are increased from day 7 until at least day 28 [12]. Emerging evidences indicate that HMGB1 is an important factor that links gut BT and sepsis, and extracellular histones are also important factors that significantly contribute to MOF in ALF. In this manuscript, we review the current understanding of HMGB1 and histones in ALF.

2. The Role of HMGB1 in ALF

2.1. HMGB1 is a Typical Alarmin. Endogenous danger-associated molecular patterns (DAMPs) are also known as alarmins, which signal cellular damage and activate the innate immune system [13]. Alarmins share the following features: (a) rapid release from cells in response to infection or tissue damage, (b) chemoattraction and activation of antigen-presenting cells, and (c) activation of innate and adaptive immunity [14]. HMGB1 is a typical alarmin [14].

2.2. Passive Release. HMGB1 can be passively released by necrotic/damaged cells or actively secreted by immunocompetent cells [15]. Under necrotic condition, contents of the cytosol are dispersed into the extracellular space due to cellular distress or damage [16]. In necrotic cells, HMGB1 dissociates from chromatin and is released from cells to trigger inflammation. However, HMGB1 remains bound to chromatin and fails to promote inflammation in cells undergoing apoptotic or programmed cell death, in which cytosolic contents are sequestered and not "seen" by innate immune cells [16].

2.3. Active Secretion. In response to proinflammatory stimuli such as LPS, HMGB1 can be actively secreted by immunocompetent cells. This active secretion occurs through a two-step process. First, HMGB1 is translocated out of the nucleus to the cytoplasm after JAK/STAT1-regulated hyper-acetylation of lysine residues located in the A and B box domains [17]. Once in the cytoplasm, HMGB1 is actively secreted [17]. The active secretion of HMGB1 follows a nonclassical, vesicle-mediated pathway [18].

2.4. Redox State and Extracellular Functions. HMGB1 contains three conserved redox-sensitive cysteines (C23, C45, and C106), and posttranslational modification (oxidation) of these cysteines determines the bioactivity of extracellular HMGB1 [19]. The cytokine-stimulating activity of HMGB1 requires C23 and C45 to be in a disulfide linkage, while C106 remains in a reduced state. This disulfide HMGB1 can bind and signal via TLR4/MD-2 complex to induce cytokine release in macrophage [19]. Moreover, binding of HMGB1 to TLR4 depends on reduced Cys106 [20]. If all three cysteines are in reduced form, this all-thiol HMGB1 has chemotactic activity. This form is present under basal conditions. Under inflammatory conditions, this all-thiol HMGB1 is released and forms a heterocomplex with the chemokine CXCL12 to interact with the chemokine receptor CXCR4 to promote cell migration, but no inflammatory cytokine secretion. The third form of HMGB1 occurs under a state of complete oxidation wherein each cysteine is fully oxidized to a sulfonyl form and is not associated with any biological function [19]. Hyperacetylation of HMGB1 shifts its equilibrium from a predominant nuclear location toward a cytosolic and subsequent extracellular presence. Hence, posttranslational modifications of HMGB1 determine its role in inflammation and immunity [19].

2.5. ALF Releases HMGB1 as a Signal of Inflammation. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity [21], and the mode of the cell death typically follows one of the two patterns: necrosis or apoptosis [21]. In a clinical trial, HMGB1 represents the circulating indicator of necrosis during acetaminophen hepatotoxicity; full-length and caspase-cleaved keratin-18 are circulating markers of necrosis and apoptosis; hyperacetylated HMGB1 is a serum indicator of pyroptosis and immune cell activation [22, 23]. Elevations in plasma HMGB1 and keratin-18 can serve as mechanistic biomarkers to provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to a hospital [22]. Increased total and acetylated HMGB1 and full-length keratin-18 are associated with worse prognosis during clinical acetaminophen hepatotoxicity [23]. HMGB1 can be released readily from necrotic or damaged cells to serve as a signal for inflammation [16, 24]. HMGB1 plays an important role in modulating inflammatory cascade in activated macrophages: HMGB1 stimulates macrophages to release TNF-[alpha] and IL-6 [20, 25]. HMGB1 is a potent mediator of systemic inflammation in sepsis [26].

2.6. HMGB1 Contributes to Multiple Organ Injuries. HMGB1 contributes to liver injury in experimental ischemia-reperfusion [27]. Exogenous HMGB1 injection can induce evident liver injury in mice [28]. HMGB1 impairs hepatocyte regeneration and blockade of HMGB1 improves hepatocyte regeneration in mice challenged with acetaminophen overdose [29]. A partly humanized anti-HMGB1 monoclonal antibody attenuates acetaminophen hepatotoxicity and postinjury inflammation in mice [30]. HMGB1 is released into the serum at early stage of D-galactosamine/LPS-induced ALF, and HMGB1 acts synergistically with TNF-[alpha] to promote the inflammatory liver injury; this detrimental effect can be reversed by monoclonal antibodies against HMGB1 and TNF-[alpha] [31]. Inhibition of sphingosine kinase-1 ameliorates experimental ALF by reducing high-mobility group box 1 cytoplasmic translocation in liver cells [32]. HMGB1 contributes to renal ischemia-reperfusion injury [33], sepsis-induced kidney injury [34], and severe acute pancreatitis-related kidney injury [35]. HMGB1 also significantly contributes to hemorrhagic shock-related acute lung injury (ALI) [36], hyperoxia-induced ALI [37], and severe acute pancreatitis-related ALI [38].

2.7. HMGB1 Contributes to Gut MucosalInjury and Mediates Gut BT in ALF. Gut mucosal injury and intestinal BT in ALF is particularly important because the intestine is the biggest reservoir of bacteria in the body and leakage of bacteria or microbial products, notably LPS, from the lumen of the gut into the systemic circulation, leads to initiation or amplification of a systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). Therefore, the leaky gut is thought to be the "motor" that drives the development of MODS [39].

The serum HMGB1 concentrations are significantly increased in mice challenged with acetaminophen overdose [29, 40]. ALF patients also have high concentrations of circulating HMGB1, and the circulating HMGB1 levels are associated with disease severity [41, 42]. The circulating HMGB1 contributes to gut mucosal hyperpermeability and induces evident BT in experimental hemorrhagic shock and reperfusion [43], and exogenous HMGB1 injection can induce gut hyperpermeability and BT in mice [28]. Except from the circulating HMGB1, bile HMGB1 might also significantly contribute to intestinal mucosa injury and induce evident BT in ALF, because hepatitis E virus-related ALF is associated with significantly increased circulating LPS [44], and LPS injection reduces 40% of bile flow in rats [45]; adequate bile is required to maintain gut epithelial tight junction and intestinal bacterial homeostasis [46]; decreased gut luminal bile volume not only impairs intestinal tight junction but also changes intestinal bacterial homeostasis to facilitate BT [46, 47]. In addition, LPS injection (to normal animals) markedly increases bile TNF-a and HMGB1 levels, which can induce gut mucosal hyperpermeability and evident BT in mice [45], and this detrimental effect can be reversed by neutralization of the bile HMGB1 [45].

Experimental hepatotoxicity is associated with high incidence of gut derived gram-negative bacterial infection [9,40]. Acetaminophen overdose can induce evident gut BT and severe intestinal mucosal injury in mice [40], and gut bacteria can adhere to the injured mucosa, which is necessary but not sufficient to induce gut BT [40], because blockade of HMGB1 reduces 85% of gut BT, but it does not decrease gut mucosal permeability in experimental acetaminophen overdose [40]. This indicates that BT is mediated (at least partly) by HMGB1 and BT is likely an active "transcellular" procedure in which HMGB1 is also needed.

2.8. BT Induces/Triggers Systemic Inflammation, Which Leads to MOF in ALF. Gut BT (or gut-derived LPS) induces/triggers systemic inflammation in critical illness [48, 49]. SIRS can lead to MOF in ALF [7]. Sepsis is a typical example of SIRS triggered by infection [50]. Therefore, HMGB1 seems to be an important factor that links BT and SIRS in ALF.

3. The Role of Extracellular Histones in ALF

3.1. ALF Patients/Animals Have High Concentrations of Circulating Histones. ALF has a large number of hepatocyte death [21]. The necrotic tissue/the dying hepatocytes release HMGB1 and histones [50], which can contribute to the high concentrations of circulating histones in animals challenged with concanavalin A and acetaminophen overdose to induce two different acute fatal liver injury models [50]. Circulating histones are significantly increased in ALF patients and in patients with HBV-related acute-on-chronic liver failure, and the levels of circulating histones are correlated with disease severity and mortality [51, 52]. ALF patients also have elevated plasma histone-associated DNA levels [53]. DAMPs activate innate immune cells in the liver and the circulation, subsequently leading to tissue inflammation and SIRS [53, 54].

3.2. Extracellular Histones Contribute to Multiple Organ Injuries in ALF. Histones are important structural elements of nuclear chromatin and regulate gene transcription [54]; however, extracellular histones are cell toxic to host cells [50, 54] and elicit immunostimulatory effect that can induce multiple organ injuries [50, 53-55]. Circulating histones exacerbate inflammation in mice with ALF [56]. The sera (containing high levels of histones) from ALF patients can induce L02 cell (hepatocyte) death and stimulate U937 cells (monocytes) to release inflammatory cytokines; these detrimental effects can be abolished by non-anticoagulant heparin that can bind histones, suggesting that circulating histones might be the major mediators of systemic inflammation and cellular injury in patients with ALF [51]. The circulating angiopoietin-2 levels, a marker of tissue endothelial dysfunction and leakage, are markedly increased in ALF patients [53], and this might be due to the toxicity of extracellular histones in ALF patients. Extracellular histones contribute to acute fatal liver injury via TLR 2 and TLR4 receptors, and neutralization of histones can ameliorate fatal liver injury in mice [50]. The levels of circulating histones are significantly higher after liver ischemia/reperfusion, the endogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9, and neutralization of histone significantly protects against injury [57]. Extracellular histones can induce microvascular endothelial injury, and the TLR2/4-mediated inflammation leads to acute tubular necrosis in experimental acute kidney injury [58, 59]. Extracellular histones can injure endothelial cells to cause microvascular thrombosis and hemorrhage in experimental acute lung injury [60]. Histones also contribute to experimental acute brain injury, and neutralization of histones can reduce the infarct size [61]. Histone H4 and increased circulating neutrophil extracellular traps (NETs) can activate platelets; this may cause microvascular thrombosis in sepsis [50, 55, 59, 62]. HMGB1 may induce the same biological response [63]. Extracellular histones kill endothelial cells and are one of the major mediators of death in sepsis [55].

4. Conclusions

HMGB1 and extracellular histones play a significant role in inducing systemic inflammation and MOF in ALF; neutralization of HMGB1 and histones may present a novel therapy to treat ALF.

A graphical abstract is provided as the Supplementary material available online at 5928078.

ALF:     Acute liver failure
MOF:     Multiple organ failure
SIRS:    Systemic inflammatory response syndrome
BT:      Bacterial translocation
HMGB1:   High mobility group box 1
NETs:    Neutrophil extracellular traps
DAMP:    Damage-associated molecular pattern
TLR:     Toll-like receptor
APAP:    Acetaminophen
MODS:    Multiple organ dysfunction syndrome
MD-2:    Myeloid differentiation factor 2
LPS:     Lipopolysaccharide
D-GalN:  D-galactosamine
Sphk1:   Sphingosine kinase 1.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors' Contributions

Runkuan Yang designed and drafted the manuscript. Xiaoping Zou carried out the literature search and drafted the manuscript. Tor Inge Tonnessen drafted and revised the manuscript.


This investigation was partly supported by Sigrid Juselius Funding in Finland and South-Eastern Norway Regional Health Authority, Grant no. 2013121.


[1] J. Polson and W. M. Lee, "American association for the study of liver disease. AASLD position paper: the management of acute liver failure," Hepatology, vol. 41, pp. 1179-1197, 2005.

[2] W. Bernal and J. Wendon, "Acute liver failure," The New England Journal of Medicine, vol. 369, pp. 2525-2534, 2013.

[3] W. M. Lee, "Acute liver failure," Seminars in Respiratory and Critical Care Medicine, vol. 33, pp. 36-45, 2012.

[4] W. Bernal, G. Auzinger, A. Dhawan, and J. Wendon, "Acute liver failure," Lancet, vol. 376, pp. 190-201, 2010.

[5] A. M. Larson, "Diagnosis and management of acute liver failure," Current Opinion in Gastroenterology, vol. 26, pp. 214-221, 2010.

[6] A. Reuben, D. G. Koch, W. M. Lee, and Acute liver failure study Group, "Drug-induced acute liver failure: results of a U.S. multicenter, prospective study," Hepatology, vol. 52, pp. 2065-2076, 2010.

[7] N. Rolando, J. Wade, M. Davalos, J. Wendon, J. Philpott-Howard, and R. Williams, "The systemic inflammatory response syndrome in acute liver failure," Hepatology, vol. 32, pp. 734-739, 2000.

[8] J. Vaquero, J. Polson, C. Chung et al., "Infection and the progression of hepatic encephalopathy in acute liver failure," Gastroenterology, vol. 125, pp. 755-764, 2003.

[9] F. B. Kasravi, L. Q. Wang, X. D. Wang, G. Molin, S. Bengmark, and B. Jeppsson, "Bacterial translocation in acute liver injury induced by D-galactosamine," Hepatology, vol. 23, pp. 97-103, 1996.

[10] R. Yang, X. Zou, M. L. Koskinen, and J. Tenhunen, "Ethyl pyruvate reduces liver injury at early phase but impairs regeneration at late phase in acetaminophen overdose," Critical Care, vol. 16, p. R9, 2012.

[11] Y. Zhang, W. Li, S. Zhu et al., "Tanshinone IIA sodium sulfonate facilitates endocytic HMGB1 uptake," Biochemical Pharmacology, vol. 84, pp. 1492-1500, 2012.

[12] S. I. Valdes-Ferrer, J. Papoin, M. E. Dancho et al., "HMGB1 mediates anemia of inflammation in murine sepsis survivors," Molecular Medicine, vol. 21, no. 1, pp. 951-958, 2015.

[13] M. E. Bianchi, "DAMPs, PAMPs and alarmins: all we need to know about danger," Journal of Leukocyte Biology, vol. 81, pp. 1-5, 2007.

[14] D. S. Pisetsky, H. Erlandsson-Harris, and U. Andersson, "High-mobility group box protein1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease," Arthritis Research & Therapy, vol. 10, p. 209, 2008.

[15] H. Yang, H. Wang, Y. A. Levine et al., "Identification of CD163 as an anti-inflammatory receptor for HMGB1-haptoglobin complexes," JCI Insight, vol. 1, 2016.

[16] P. Scaffidi, T. Misteli, and M. E. Bianchi, "Release of chromatin protein HMGB1 by necrotic cells triggers inflammation," Nature, vol. 418, pp. 191-195, 2002.

[17] B. Lu, D. J. Antoine, K. Kwan et al., "JAK/STAT1signaling promotes HMGB1 hyperacetylation and nuclear translocation," Proceedings of the National Academy of Sciences of the United States of America, vol. 111, pp. 3068-3073, 2014.

[18] S. Gardella, C. Andrei, D. Ferrera et al., "The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway," EMBO Reports, vol. 3, pp. 995-1001, 2002.

[19] H. Yang, D. J. Antoine, U. Andersson, and K. J. Tracey, "The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis and chemotaxis," Journal of Leukocyte Biology, vol. 93, pp. 865-873, 2013.

[20] H. Yang, H. S. Hreggvidsdottir, K. Palmblad et al., "A critical cysteine is required for HMGB1 binding to toll-like receptor 4 and activation of macrophage cytokine release," PNAS, vol. 26, pp. 11942-11947, 2010.

[21] A. Rutherford and R. T. Chung, "Acute liver failure: mechanisms of hepatocyte injury and regeneration," Seminars in Liver Disease, vol. 28, pp. 167-174, 2008.

[22] D. J. Antoine, J. W. Dear, P. S. Lewis et al., "Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital," Hepatology, vol. 58, pp. 777-787, 2013.

[23] D. J. Antoine, R. E. Jenkins, J. W. Dear et al., "Molecular forms of HMGB1 and kerarin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity," Journal of Hepatology, vol. 56, pp. 1070-1079, 2012.

[24] M. E. Bianchi and A. A. Manfredi, "High mobility group B1 (HMGB1) protein at the crossroads between innate and adaptive immunity," Immunological Reviews, vol. 220, pp. 35-46, 2007.

[25] D. Gero, P. Szoleczky, K. Modis et al., "Identification of pharmacological modulators of HMGB1-induced inflammatory response by cell-based screening," PloS One, vol. 8, article e65994, 2013.

[26] B. Cai, E. A. Deitch, and L. Ulloa, "Novel insights for systemic inflammation in sepsis and hemorrhage," Mediators of Inflammation, vol. 2010, Article ID 642462, 2010.

[27] H. Huang, S. Tohme, A. B. Al-khafaji et al., "Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury," Hepatology, vol. 62, pp. 600-614, 2015.

[28] P. L. Sappington, R. Yang, H. Yang, K. J. Tracey, R. L. Deluder, and M. P. Fink, "HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice," Gastroenterology, vol. 123, pp. 790-802, 2002.

[29] R. Yang, S. Zhang, A. Cotoia, N. Oksala, S. Zhu, and J. Tenhunen, "High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity," BMC Gastroenterology, vol. 12, p. 45, 2012.

[30] P. Lundback, J. D. Lea, A. Sowinska et al., "A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice," Hepatology, vol. 64, pp. 1699-1710, 2016.

[31] W. Wang, L. Sun, Y. Deng, and J. Tang, "Synergistic effects of antibodies against high-mobility group box 1 and tumor necrosis factor-a on D- (+)-galactosamine hydrochloride/lipopolysaccharide-induced acute liver failure," The FEBS Journal, vol. 280, pp. 1409-1419, 2013.

[32] Y. C. Lei, L. L. Yang, W. Li, P. Luo, and P. F. Zheng, "Inhibition of sphingosine kinase 1 ameliorates acute liver failure by reducing high-mobility group box 1 cytoplasmic translocation in liver cells," World Journal of Gastroenterology, vol. 21, pp. 13055-13063, 2015.

[33] A. Lau, S. Wang, W. Liu, A. Haig, Z. Zhang, and A. M. Jevnikar, "Glycyrrhizic acid ameliorates HMGB1-mediated cell death and inflammation after renal ischemia reperfusion injury," American Journal of Nephrology, vol. 40, pp. 84-95, 2014.

[34] Y. Hu, M. H. Pai, C. L. Yeh, Y. C. Hou, and S. L. Yeh, "Glutamine administration ameliorates sepsis-induced kidney injury by downregulating the high-mobility group box protein-1-mediated pathway in mice," American Journal of Physiology. Renal Physiology, vol. 302, pp. F150-F158, 2012.

[35] H. Sawa, T. Ueda, Y. Takeyama et al., "Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis," World Journal of Gastroenterology, vol. 12, pp. 7666-7670, 2006.

[36] R. L. Kao, X. Xu, A. Xenocostas et al., "Induction of acute lung inflammation in mice with hemorrhagic shock and reperfusion: role of HMGB1," Journal of Inflammation (London, England), vol. 11, pp. 30-37, 2014.

[37] M. Entezari, M. Javdan, D. J. Antoine et al., "Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury," Redox Biology, vol. 2, pp. 314-322, 2014.

[38] Z. Luan, X. Zhang, X. Yin et al., "Downregulation of HMGB1 protects against the development of acute lung injury after severe acute pancreatitis," Immunobiology, vol. 218, pp. 1261-1270, 2013.

[39] M. P. Fink, "Leaky gut hypothesis: a historical perspective," Critical Care Medicine, vol. 18, pp. 579-580, 1990.

[40] R. Yang, X. Zou, J. Tenhunen et al., "Neutralization of HMGB1 is associated with bacterial translocation during acetaminophen hepatotoxicity," BMC Gastroenterology, vol. 14, p. 66, 2014.

[41] M. Majumdar, R. Ratho, Y. Chawla, and M. P. Singh, "High levels of circulating HMGB1 as a biomarker of acute liver failure in patients with hepatitis E," Liver International, vol. 33, pp. 1341-1348, 2013.

[42] G. Oshima, M. Shinoda, M. Tanabe et al., "Increased plasma levels of high mobility group box 1 in patients with acute liver failure," European Surgical Research, vol. 48, pp. 154-162, 2012.

[43] R. Yang, T. Harada, K. P. Mollen et al., "Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock," Molecular Medicine, vol. 12, pp. 105-114, 2006.

[44] F. Wu, M. Wang, and D. Tian, "Serum from patients with hepatitis E virus-related acute liver failure induces human liver cell apoptosis," Experimental and Therapeutic Medicine, vol. 7, pp. 300-304, 2014.

[45] R. Yang, K. Miki, N. Oksala et al., "Bile high mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia," American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 297, pp. R362-R369, 2009.

[46] R. Yang, T. Harada, J. Li et al., "Bile modulates intestinal epithelial barrier function via extracellular signal related kinase % dependent mechanism," Intensive Care Medicine, vol. 31, pp. 709-717, 2005.

[47] Y. Ogata, M. Nishi, H. Nakayama, T. Kuwahara, Y. Ohnishi, and S. Tashiro, "Role of bile in intestinal barrier function and its inhibitory effect on bacterial translocation in obstructive jaundice in rats," The Journal of Surgical Research, vol. 115, pp. 18-23, 2003.

[48] M. Fanous, A. J. Phillips, and J. A. Windsor, "Mesenteric lymph: the bridge to future management of critical illness," JOP: Journal of the Pancreas, vol. 8, pp. 374-399, 2007.

[49] N. Runkel, "Bacterial translocation in acute pancreatitis," Digestive Surgery, vol. 13, pp. 269-272, 1996.

[50] J. Xu, X. Zhang, M. Monestier, N. L. Esmon, and C. T. Esmon, "Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury," Journal of Immunology, vol. 187, pp. 2626-2631, 2011.

[51] Z. Wen, Z. Lei, L. Yao et al., "Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure," Cell Death & Disease, vol. 7, article e2391, 2016.

[52] X. Li, C. Gou, L. Yao et al., "Patients with HBV-related acute-on-chronic liver failure have increased concentrations of extracellular histones aggravating cellular damage and systemic inflammation," Journal of Viral Hepatitis, vol. 24, pp. 59-67, 2017.

[53] F. S. Larsen, L. E. Schmidt, C. Bernsmeier et al., "High-volume plasma exchange in patients with acute liver failure: an open randomized controlled trial," Journal of Hepatology, vol. 64, pp. 69-78, 2016.

[54] R. Allam, S. V. R. Kumar, M. N. Darisipudi, and H. J. Anders, "Extracellular histones in tissue injury and inflammation," Journal of Molecular Medicine, vol. 92, pp. 465-472, 2014.

[55] J. Xu, X. Zhang, R. Pelayo et al., "Extracellular histones are major mediators of death in sepsis," Nature Medicine, vol. 15, pp. 1318-1321, 2009.

[56] Z. Wen, Y. Liu, F. Li et al., "Circulating histones exacerbate inflammation in mice with acute liver failure," Journal of Cellular Biochemistry, vol. 114, pp. 2384-2391, 2013.

[57] H. Huang, J. Evankovich, W. Yan et al., "Endogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9 in mice," Hepatology, vol. 54, pp. 999-1008, 2011.

[58] R. Allam, C. R. Scherbaum, M. N. Darisiputi et al., "Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4," Journal of the American Society of Nephrology, vol. 23, pp. 1375-1388, 2012.

[59] D. L. Rosin and M. D. Okusa, "Dying cells and extracellular histones in AKI: beyond a NET effect?" Journal of the American Society of Nephrology, vol. 23, pp. 1275-1277, 2012.

[60] M. Bosmann, J. J. Grailer, R. Ruemmler et al., "Extracellular histones are essential effector of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury," The FASEB Journal, vol. 27, pp. 5010-5021, 2013.

[61] S. F. De Meyer, G. L. Suidan, T. A. Fuchs, M. Monestier, and D. D. Wagner, "Extracellular chromatin is an important mediator of ischemic stroke in mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, pp. 1884-1891, 2012.

[62] R. Yang, J. Tenhunen, and T. I. Tonnessen, "HMGB1 and histones play a significant role in inducing systemic inflammation and multiple organ dysfunctions in severe acute pancreatitis," International Journal of Inflammation, vol. 2017, Article ID 1817564, 2017.

[63] J. M. Tadie, H. B. Bae, S. Jiang et al., "HMGB1 promotes neutrophil extracellular trap formation through interactions with toll-like receptor 4," American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 304, pp. L342-L349, 2013.

Runkuan Yang, (1,2,3) Xiaoping Zou, (4) Jyrki Tenhunen, (1,5) and Tor Inge Tonnessen (3,6)

(1) Department of Intensive Care Medicine, Tampere University Hospital, University of Tampere, 10 Bio Katu, 33014 Tampere, Finland

(2) Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA 15261, USA

(3) Department of Emergencies and Critical Care, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway

(4) Department of Gastroenterology, Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Street, Nanjing 210008, China

(5) Department of Surgical Science, Anesthesiology and Intensive Care Medicine, Uppsala University, 751 85 Uppsala, Sweden

(6) Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway

Correspondence should be addressed to Runkuan Yang;

Received 25 November 2016; Revised 27 February 2017; Accepted 8 May 2017; Published 13 June 2017

Academic Editor: Jose Crispin
COPYRIGHT 2017 Hindawi Limited
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Yang, Runkuan; Zou, Xiaoping; Tenhunen, Jyrki; Tonnessen, Tor Inge
Publication:Mediators of Inflammation
Article Type:Report
Date:Jan 1, 2017
Previous Article:Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by A[[beta].sub.42] through Nrf2-Related...
Next Article:Interluekin-35 in Asthma and Its Potential as an Effective Therapeutic Agent.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters