Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure

Abstract

Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.

Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

“…Histones have been shown to induce thrombocytopenia in mice, 34 and have been implicated in thrombocytopenia in patients admitted to intensive care. 35 As levels of circulating histones are slightly elevated in patients with cirrhosis, and substantially elevated in patients with acute liver failure, 36 the role of histones in the thrombocytopenia of liver disease should be further explored. Next to their thrombocytopenia, patients with cirrhosis may have a prolonged skin bleeding time indicative of platelet defects.…”

VEGF mitigates histone-induced pyroptosis in the remote liver injury associated with renal allograft ischemia–reperfusion injury in rats

“…It is suggested that histone mediates cell death and inflammation by binding to Toll‐like receptors (eg, TLR‐4 and TLR‐9) 14. Activation of TLRs may trigger the downward cascade including the inflammasome to activate pyroptosis and produce proinflammatory cytokines, exacerbating the injury and causing a systemic response 15, 16…”

“…14 Activation of TLRs may trigger the downward cascade including the inflammasome to activate pyroptosis and produce proinflammatory cytokines, exacerbating the injury and causing a systemic response. 15,16 Pyroptosis is a lytic type of cell death and a form of regulated necrosis that is inherently associated with inflammation and distinguished from other forms of cell death by the associated secretion of interleukin (IL)-1β after caspase-1 activation. The cellular processes that occur during pyroptosis include nuclear condensation, DNA damage, cell swelling, and, finally, cell lysis, with the subsequent release of IL-1β and are reliant on intracellular sensors of bacterial products and formation of the inflammasome.…”

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

“…LA-4,94 94 mouse type II pneumocytes, 98 L02 hepatocytes,100 CHO-K1,101 CHO-A745101 Calcium influx, cytokine (IL-1β, IL-6, IL-10, TNFa) production (A549, BEAS-2B, LA-4) and cell death (PI/ LDH; all cell types)…”