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.

We read with great interest the recent Gut publication by Schepers et al 1 reporting no association between the time of onset or duration of persistent organ failure (POF, >48 hours, distinguished from transient organ failure second week) caused by infected pancreatic necrosis (IPN).2 Patients with early fulminant POF have been considered to have a higher mortality than those developing POF later,3–6 and those with POF in combination with IPN to have a higher mortality than those with POF alone.7 The findings from Schepers et al 1 have challenged these views but require confirmation. We have determined whether their findings are applicable to our AP patient populations. We analysed 2145 and 939 patients with AP from retrospective (single centre) and prospective cohorts (multicentre), respectively, who were admitted ≤48 hours of symptoms onset (online supplementary table 1). There were 469 (21.9%) and 132 (14.1%) patients …

The level of hypertriglyceridaemia (HTG) at which the risk of acute pancreatitis (AP) increases and the impact of HTG on AP attributable to other aetiologies remains unclear. We compared clinical outcomes of patients admitted within 48 h of the onset of abdominal pain from a first episode of AP and admission serum triglyceride levels of either <5.65 mmol/l (<500 mg/dl) or ≥5.65 to <11.3 mmol/l (moderate HTG) or ≥11.3 mmol/l (≥1000 mg/dl, severe HTG). Among a cohort of 1,233 patients with AP there were significant progressive increases in all major deleterious clinical outcomes including mortality (all Ptrend < 0.05) that were directly dependent on admission triglyceride levels. Outcomes were improved by earlier presentation (<24 h compared to 24-48 h from abdominal pain onset). Patients with severe HTG and a concomitant aetiology (n = 68) had significantly more persistent organ failure, pancreatic necrosis and longer hospital stays (P < 0.05) than those with severe HTG alone (n = 206). There appears to be an association between HTG grade and the severity of AP. Severe HTG significantly increased the severity of AP, over AP attributable to other aetiologies. Moderate as well as severe HTG can be used as a criterion for the diagnosis of HTG-associated AP.

Early prediction of acute pancreatitis severity remains a challenge. Circulating levels of histones are raised early in mouse models and correlate with disease severity. It was hypothesized that circulating histones predict persistent organ failure in patients with acute pancreatitis. Consecutive patients with acute pancreatitis fulfilling inclusion criteria admitted to Royal Liverpool University Hospital were enrolled prospectively between June 2010 and March 2014. Blood samples were obtained within 48 h of abdominal pain onset and relevant clinical data during the hospital stay were collected. Healthy volunteers were enrolled as controls. The primary endpoint was occurrence of persistent organ failure. The predictive values of circulating histones, clinical scores and other biomarkers were determined. Among 236 patients with acute pancreatitis, there were 156 (66·1 per cent), 57 (24·2 per cent) and 23 (9·7 per cent) with mild, moderate and severe disease respectively, according to the revised Atlanta classification. Forty-seven healthy volunteers were included. The area under the receiver operating characteristic (ROC) curve (AUC) for circulating histones in predicting persistent organ failure and mortality was 0·92 (95 per cent c.i. 0·85 to 0·99) and 0·96 (0·92 to 1·00) respectively; histones were at least as accurate as clinical scores or biochemical markers. For infected pancreatic necrosis and/or sepsis, the AUC was 0·78 (0·62 to 0·94). Histones did not predict or correlate with local pancreatic complications, but correlated negatively with leucocyte cell viability (r = –0·511, P = 0·001). Quantitative assessment of circulating histones in plasma within 48 h of abdominal pain onset can predict persistent organ failure and mortality in patients with acute pancreatitis. Early death of immune cells may contribute to raised circulating histone levels in acute pancreatitis.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.