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

Abstract

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.

Effects of different periods of gastric ischemia on liver as a remote organ

“…Gastric ischemia, such as the gut ischemia, unleashes a distributive shock due to the increase in the vascular permeability and reduction in aorta blood flow 9 and a local inflammatory process which extends to other organs and can be prolonged, giving rise to the onset of MODS 10 . Liver failure is a common complication in critical diseases and contributes to the worsening of patient prognosis [10][11][12][13][14][15] . The liver plays an important role in the immune, endocrine, and metabolic control, and is frequently damaged in medical conditions of shock, sepsis and systemic inflammation.…”

Practical guide to the management of acute pancreatitis

“…There is also evidence that ethanol increases pancreatic ductal pressure favouring retrograde flow and intra-pancreatic enzymatic activation 10. It is likely that the ischaemia-reperfusion injury plays a role in the development of AP, which is supported by the importance of early aggressive fluid resuscitation 11. Microvascular changes may lead to increased pancreatic vascular permeability, oedema, haemorrhage and pancreatic necrosis.…”

Role of serum high-motility group box-1 (HMGB1) concentration as a prognostic factor in canine acute pancreatitis

“…Mild AP is a localized process presenting uncomplicated full recovery, but severe AP (SAP) with necrosis, although localized, can cause systemic in ammatory response syndrome (SIRS) resulting in poorer responses. Extracellular HMGB1 is considered to be a novel pro-in ammatory cytokine in humans [3], and several studies have signi cantly contributed to elucidating its pathophysiologic role in SAP [4,5]. HMGB1 is initially produced by pancreatic and peritoneal macrophages in SAP in response to in ammation and is then partially released into the blood, thereby damaging remote organs.…”