BACKGROUND: Tissue injury leads to the release of DAMPs (damage-associated molecular patterns) that may drive a sterile inflammatory response; however, the role of extracellular histone levels after traumatic injury remains unexplored. We hypothesized that extracellular histone levels would be increased and associated with poor outcomes after traumatic injury. METHODS: In this prognostic study, plasma was prospectively collected from 132 critically injured trauma patients on arrival and 6 hours after admission to an urban Level I trauma intensive care unit. Circulating extracellular histone levels and plasma clotting factors were assayed and linked to resuscitation and outcome data. RESULTS: Of 132 patients, histone levels were elevated to a median of 14.0 absorbance units (AU) on arrival, declining to 6.4 AU by 6 hours. Patients with elevated admission histone levels had higher ISS (Injury Severity Score), lower admission GCS (Glasgow Coma Scale) score, more days of mechanical ventilation, and higher incidences of multiorgan failure, acute lung injury, and mortality (all p ≤ 0.05). Histone levels correlated with prolonged international normalized ratio and partial thromboplastin time, fibrinolytic markers D-dimer and tissue-type plasminogen activator, and anticoagulants tissue factor pathway inhibitor and activated protein C (aPC; all p < 0.03). Increasing histone level from admission to 6 hours was a multivariate predictor of mortality (hazard ratio, 1.005; p = 0.013). When aPC level trends were included, the impact of histone level increase on mortality was abrogated (p = 0.206) by a protective effect of increasing aPC levels (hazard ratio, 0.900; p = 0.020). CONCLUSION: Extracellular histone levels are elevated in response to traumatic injury and correlate with fibrinolysis and activation of anticoagulants. An increase in histone levels from admission to 6 hours is predictive of mortality, representing evidence of ongoing release of intracellular antigens similar to that seen in sepsis. Concomitant elevation of aPC abrogates this effect, suggesting a possible role for aPC in mitigating the sterile inflammatory response after trauma through the proteolysis of circulating histones. LEVEL OF EVIDENCE: Prognostic study, level III. Copyright 2012 by Lippincott Williams & Wilkins
BACKGROUND: Tissue injury leads to the release of DAMPs (damage-associated molecular patterns) that may drive a sterile inflammatory response; however, the role of extracellular histone levels after traumatic injury remains unexplored. We hypothesized that extracellular histone levels would be increased and associated with poor outcomes after traumatic injury. METHODS: In this prognostic study, plasma was prospectively collected from 132 critically injured trauma patients on arrival and 6 hours after admission to an urban Level I trauma intensive care unit. Circulating extracellular histone levels and plasma clotting factors were assayed and linked to resuscitation and outcome data. RESULTS: Of 132 patients, histone levels were elevated to a median of 14.0 absorbance units (AU) on arrival, declining to 6.4 AU by 6 hours. Patients with elevated admission histone levels had higher ISS (Injury Severity Score), lower admission GCS (Glasgow Coma Scale) score, more days of mechanical ventilation, and higher incidences of multiorgan failure, acute lung injury, and mortality (all p ≤ 0.05). Histone levels correlated with prolonged international normalized ratio and partial thromboplastin time, fibrinolytic markers D-dimer and tissue-type plasminogen activator, and anticoagulants tissue factor pathway inhibitor and activated protein C (aPC; all p < 0.03). Increasing histone level from admission to 6 hours was a multivariate predictor of mortality (hazard ratio, 1.005; p = 0.013). When aPC level trends were included, the impact of histone level increase on mortality was abrogated (p = 0.206) by a protective effect of increasing aPC levels (hazard ratio, 0.900; p = 0.020). CONCLUSION: Extracellular histone levels are elevated in response to traumatic injury and correlate with fibrinolysis and activation of anticoagulants. An increase in histone levels from admission to 6 hours is predictive of mortality, representing evidence of ongoing release of intracellular antigens similar to that seen in sepsis. Concomitant elevation of aPC abrogates this effect, suggesting a possible role for aPC in mitigating the sterile inflammatory response after trauma through the proteolysis of circulating histones. LEVEL OF EVIDENCE: Prognostic study, level III. Copyright 2012 by Lippincott Williams & Wilkins
Authors: Mitchell Jay Cohen; Mariah Call; Mary Nelson; Carolyn S Calfee; Charles T Esmon; Karim Brohi; Jean Francois Pittet Journal: Ann Surg Date: 2012-02 Impact factor: 12.969
Authors: P I Johansson; A M Sørensen; A Perner; K-L Welling; M Wanscher; C F Larsen; S R Ostrowski Journal: J Thromb Haemost Date: 2012-02 Impact factor: 5.824
Authors: Edward J Kerschen; José A Fernandez; Brian C Cooley; Xia V Yang; Rashmi Sood; Laurent O Mosnier; Francis J Castellino; Nigel Mackman; John H Griffin; Hartmut Weiler Journal: J Exp Med Date: 2007-09-24 Impact factor: 14.307
Authors: Tao Li; Whayoung Lee; Hidetaka Hara; Cassandra Long; Mohamed Ezzelarab; David Ayares; Hai Huang; Yi Wang; Charles T Esmon; David K C Cooper; Hayato Iwase Journal: Transplantation Date: 2017-10 Impact factor: 4.939
Authors: Devin M Boe; Brenda J Curtis; Michael M Chen; Jill A Ippolito; Elizabeth J Kovacs Journal: J Leukoc Biol Date: 2015-04-15 Impact factor: 4.962
Authors: Hala Chaaban; Ravi S Keshari; Robert Silasi-Mansat; Narcis I Popescu; Padmaja Mehta-D'Souza; Yow-Pin Lim; Florea Lupu Journal: Blood Date: 2015-01-28 Impact factor: 22.113
Authors: Ramanjaneyulu Allam; Santhosh V R Kumar; Murthy N Darisipudi; Hans-Joachim Anders Journal: J Mol Med (Berl) Date: 2014-04-06 Impact factor: 4.599
Authors: David A C Messerer; Rebecca Halbgebauer; Bo Nilsson; Hermann Pavenstädt; Peter Radermacher; Markus Huber-Lang Journal: Nat Rev Nephrol Date: 2020-09-21 Impact factor: 28.314