Septic Shock Sera Containing Circulating Histones Induce Dendritic Cell–Regulated Necrosis in Fatal Septic Shock Patients

Abstract

The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease.

Circulating nucleosomes are associated with mortality in pediatric acute respiratory distress syndrome

“…More recently, circulating histones have been implicated as mediators of endothelial and organ dysfunction in sepsis (38), and several clinical studies have demonstrated their relevance to critical illness. Histones and their parent nucleosomes have been implicated in cardiac dysfunction (4,5), renal injury (12), and dendritic cell necrosis (24). In adults with trauma, nucleosome levels correlated with trauma severity scores, with histone levels correlating with Sequential Organ Failure Assessment scores and subsequent lung injury (2), consistent with our findings in this PARDS cohort.…”

“…In five studies (3 adult sepsis, 1 adult aspiration ARDS, and 1 pediatric sepsis), nucleosome or histone levels have been demonstrated to be higher in nonsurvivors (4,12,24,40,41). In a cohort of septic adults (n ϭ 19), elevated histone H4 on day 1 predicted increased mortality at days 28 and 90 (12).…”

“…Normally located within the nucleus, nucleosomes released into the circulation act as damage-associated molecular patterns (DAMP), and have been shown to be toxic to multiple cell types (2,12,24), offering a novel mechanism linking diverse inciting insults with subsequent lung injury and organ failure. However, whether nucleosomes are associated with PARDS development or progression is unknown.…”

“…Recent studies in adult ARDS have implicated circulating nucleosomes, the histone/DNA complexes resulting from nuclear chromatin degradation released after cellular damage, as potentially pathogenic in sepsis (4,12,24,38), aspiration (41), and trauma-related ARDS (2). Normally located within the nucleus, nucleosomes released into the circulation act as damage-associated molecular patterns (DAMP), and have been shown to be toxic to multiple cell types (2,12,24), offering a novel mechanism linking diverse inciting insults with subsequent lung injury and organ failure.…”

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

“…We are now also waiting for the development of effective antihistone strategies to verify that this polycation is indeed the major "virulence factor" but maybe that histone does not function on its own, but in synergy with additional agonists. The following recent publications on histone and sepsis are worth reading [51][52][53][54][55][56][57][58][59][60][61].…”