Circulating Histone Levels Reflect Disease Severity in Animal Models of Acute Pancreatitis

Ou, Xilong; Cheng, Zhaojun; Liu, Tingting; Tang, Zhongming; Huang, Wei; Szatmary, Peter; Toh, Cheng Hock; Zhang, Nan; Wang, Guozheng

doi:10.1097/mpa.0000000000000416

Cited by 36 publications

(35 citation statements)

References 38 publications

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“…84,[86][87][88] However, circulating histone levels increase upon injury of the kidneys, lung, liver, brain, and pancreases, and are thought to drive remote effects and the systemic inflammatory response syndrome during necroinflammation. [89][90][91][92] Extracellular histones also cause platelet aggregation and thrombus formation via TLR2 and TLR4. 93,94 The Necroinflammation Concept Necroinflammation depicts the autoamplification loop between cell necrosis and the inflammatory tissue response.…”

Section: Pattern-recognition Receptorsmentioning

confidence: 99%

How Kidney Cell Death Induces Renal Necroinflammation

Mulay

Kumar

Lech

et al. 2016

Seminars in Nephrology

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Section: Pattern-recognition Receptorsmentioning

confidence: 99%

How Kidney Cell Death Induces Renal Necroinflammation

Mulay

Kumar

Lech

et al. 2016

Seminars in Nephrology

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“…During gallstone and cholecystokinin-induced necrotising pancreatitis, 61 necrotic acinar cell death predominates with large volumes of histone released into the extracellular space. Oedema and inflammation alone does not result in a serum histone rise and it is likely that release of histone from acinar cells in pancreatic injury is a necrosis-dependent mechanism.…”

Section: Extracellular Histone In Acute Organ Injurymentioning

confidence: 99%

The role of extracellular histone in organ injury

et al. 2017

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Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved across species. Within the nucleus, they provide structural stability to chromatin and regulate gene expression. Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil extracellular traps, and all three can be detected in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion injury and autoimmune disease. Once in the extracellular space, histones act as damage-associated molecular pattern proteins, activating the immune system and causing further cytotoxicity. They interact with Toll-like receptors (TLRs), complement and the phospholipids of cell membranes inducing endothelial and epithelial cytotoxicity, TLR2/TLR4/TLR9 activation and pro-inflammatory cytokine/chemokine release via MyD88, NFκB and NLRP3 inflammasome-dependent pathways. Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ injury but warrant further research to inform future clinical applications.

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“…The necrotic tissue/the dying cells release HMGB1 and histones as DAMPs [57]; therefore, circulating histones are significantly increased in both SAP patients and experimental animals with SAP [20–23] and the circulating histones levels reflect the disease severity in experimental AP [21]. …”

Section: Introductionmentioning

confidence: 99%

“…These evidences indicate that both KCs and the hepatocytes are an important source of circulating HMGB1 in SAP, and the inflamed liver might play a critical role in the translation of pancreatic injury into systemic inflammation and MOD. In addition, the liver is an important organ to rapidly clear extracellular histones [21]; however, SAP can induce severe liver injury and impair its capacity of clearing histones, and this can lead to the increased circulating histones levels, which can significantly contribute multiple organ injury as described above. Therefore, the liver could be a promising therapeutic target to treat SAP.…”

Section: Introductionmentioning

confidence: 99%

HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

Yang

Tenhunen

Tønnessen

2017

International Journal of Inflammation

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Severe acute pancreatitis (SAP) starts as a local inflammation of pancreatic tissue that induces the development of multiple extrapancreatic organs dysfunction; however, the underlying mechanisms are still not clear. Ischemia-reperfusion, circulating inflammatory cytokines, and possible bile cytokines significantly contribute to gut mucosal injury and intestinal bacterial translocation (BT) during SAP. Circulating HMGB1 level is significantly increased in SAP patients and HMGB1 is an important factor that mediates (at least partly) gut BT during SAP. Gut BT plays a critical role in triggering/inducing systemic inflammation/sepsis in critical illness, and profound systemic inflammatory response syndrome (SIRS) can lead to multiple organ dysfunction syndrome (MODS) during SAP, and systemic inflammation with multiorgan dysfunction is the cause of death in experimental SAP. Therefore, HMGB1 is an important factor that links gut BT and systemic inflammation. Furthermore, HMGB1 significantly contributes to multiple organ injuries. The SAP patients also have significantly increased circulating histones and cell-free DNAs levels, which can reflect the disease severity and contribute to multiple organ injuries in SAP. Hepatic Kupffer cells (KCs) are the predominant source of circulating inflammatory cytokines in SAP, and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP; therefore, treating the liver injury is important in SAP.

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Circulating Histone Levels Reflect Disease Severity in Animal Models of Acute Pancreatitis

Abstract: Circulating histones increased significantly in necrotizing pancreatitis due to extensive pancreatic acinar cell death. Levels of circulating histones may have translational potential as a biomarker of disease severity.

Cited by 36 publications

References 38 publications

How Kidney Cell Death Induces Renal Necroinflammation

How Kidney Cell Death Induces Renal Necroinflammation

The role of extracellular histone in organ injury

HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

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