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

Abstract

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.

Depression of lncRNA NEAT1 Antagonizes LPS-Evoked Acute Injury and Inflammatory Response in Alveolar Epithelial Cells via HMGB1-RAGE Signaling

“…Stimulated Alveolar Epithelial Cells. Excessive lung inflammation is a proverbial feature of sepsis-related ALI/ARDS [6,18]. Therefore, we elucidated the roles of NEAT1 in LPS-induced inflammation in AECs.…”

Damage-associated molecular patterns in trauma

“…After the concept of SIRS was created, a number of publications emerged heralding the efficacy of SIRS in predicting outcomes after trauma [34,35]. Accumulating evidence indicates that SIRS associated with MOF is the result of traumatic injury-induced either accidental or regulated cell death such as necroptosis, serving as a robust source for emission of DAMPs, while the impact of apoptosis may be presumably less significant here [36][37][38][39]. Today, it is widely accepted that DAMPs are the key predominant molecules which trigger the biological host response to trauma including SIRS, by activating and recruiting effector cells including antigen-presenting cells of the immune system [12,[40][41][42][43][44][45][46].…”

Biological Activities of Rhamnan Sulfate Extract from the Green Algae Monostroma nitidum (Hitoegusa)

“…For example, DNA and histone that are leaked out from injured or disrupted cells significantly induce inflammation in the endothelial cells, leading to the production of a large quantity of TF, VWF, and TNF-α [40]. This, in turn, accelerates blood coagulation and platelet aggregation, leading to the formation of microthrombi in the capillary of various organs and the induction of disseminated intravascular coagulation (DIC) [41], which may result in multiple-organ failure (MOF) [42] or severe bleeding. Moreover, hemolytic uremic syndrome (HUS) caused by Escherichia coli O-157 infection [43], sinusoidal obstructive syndrome (SOS)/veno-occlusive disease (VOD) [44,45], and transplantation-associated thrombotic microangiopathy (TA-TMA) [46] are all disorders or conditions that result from endothelial damage and are therefore symptoms of endothelial damage.…”