Circulating Histones Are Mediators of Trauma-associated Lung Injury

Abstract

Rationale: Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. Objectives: To investigate the pathological roles of circulating histones in trauma-induced lung injury. Methods: Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models. Measurements and Main Results: In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. Conclusions: This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.

Histone H4 Promotes Prothrombin Autoactivation

“…Infusion of intravenous histones into mice causes sepsis, thrombosis, and death (11). The concentration of histones in the blood reaches 20 M under pathological conditions (43) and is sufficient to saturate prothrombin and promote autoactivation leading to thrombin generation within few hours. Pro-longed exposure to histone H4 is equivalent to a slow infusion of small amounts of thrombin in the circulation, which eventually culminates in prothrombotic and proinflammatory effects (28).…”

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

“…Cellular injury mediated by extracellular histones has been described experimentally or in human disease of the lung,94 heart,95 liver,96 kidney31 and vascular endothelium 62. Table 2 details the effects of extracellular histones observed in specific cell types.…”

Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment

“…29 The extracellular signal-regulated kinases (ERKs) and p38 MAPK are two major classes of MAPKs that play important roles in transducing inflammatory signals. 30,31 To determine whether these two pathways are involved in the upregulation of IL-6 and IL-8 in ARPE-19 cells, we examined the activation of signaling molecules by western blotting with phospho-specific antibodies. The results showed that ERKs, p38 MAPK, and JNK were all phosphorylated by the histones (Figure 5a).…”