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.
C-reactive protein (CRP) is a major acute phase protein. Although known to interact with chromatin, nucleosomes and histones, its functional roles are not clearly understood. Using both in vitro and in vivo models and samples from patients, this study demonstrates for the first time that CRP plays important roles in reducing the toxic effects of histones released into the circulation after extensive cell death. CRP protects endothelial cells by preventing histone integration into the cell membrane and thus reducing Ca2+ influx. In vivo, circulating histones cause endothelial damage, increased microvascular permeability, coagulation activation and IL-6 secretion. The latter induces CRP production in hepatocytes to form a negative feedback loop, a possible evolutionally conserved mechanism to limit secondary damage after extensive tissue injury. However, CRP responses lagged behind the histone surge following severe trauma. This indicates a time window for histone toxicity and also for potential clinical interventions using anti-histone therapy.
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