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. 2009 Jul;32(1):17-22.
doi: 10.1097/shk.0b013e3181997173.

HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans

Erik D Peltz  1 , Ernest E Moore, Phillip C Eckels, Sagar S Damle, Yuko Tsuruta, Jeffrey L Johnson, Angela Sauaia, Christopher C Silliman, Anirban Banerjee, Edward Abraham
Affiliations

HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans

Erik D Peltz et al. Shock. 2009 Jul.

Abstract

High-mobility group box 1 (HMGB1) is a late mediator of the systemic inflammation associated with sepsis. Recently, HMGB1 has been shown in animals to be a mediator of hemorrhage-induced organ dysfunction. However, the time course of plasma HMGB1 elevations after trauma in humans remains to be elucidated. Consequently, we hypothesized that mechanical trauma in humans would result in early significant elevations of plasma HMGB1. Trauma patients at risk for multiple organ failure (ISS > or = 15) were identified for inclusion (n = 23), and postinjury plasma samples were assayed for HMGB1 by enzyme-linked immunosorbent assay. Comparison of postinjury HMGB1 levels with markers for patient outcome (age, injury severity score, units of red blood cell (RBC) transfused per first 24 h, and base deficit) was performed. To investigate whether postinjury transfusion contributes to elevations of circulating HMGB1, levels were determined in both leuko-reduced and non-leuko-reduced packed RBCs. Plasma HMGB1 was elevated more than 30-fold above healthy controls within 1 h of injury (median, 57.76 vs. 1.77 ng/mL; P < 0.003), peaked from 2 to 6 h postinjury (median, 526.18 ng/mL; P < 0.01 vs. control), and remained elevated above control through 136 h. No clear relationship was evident between postinjury HMGB1 levels and markers for patient outcome. High-mobility group box 1 levels increase with duration of RBC storage, although concentrations did not account for postinjury plasma levels. Leuko-reduced attenuated HMGB1 levels in packed RBCs by approximately 55% (P < 0.01). Plasma HMGB1 is significantly increased within 1 h of trauma in humans with marked elevations occurring from 2 to 6 h postinjury. These results suggest that, in contrast to sepsis, HMGB1 release is an early event after traumatic injury in humans. Thus, HMGB1 may be integral to the early inflammatory response to trauma and is a potential target for future therapeutics.

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Figures

Fig. 1
Fig. 1. Plasma HMGB1 concentrations in trauma patients from less than 1 to 136 h postinjury
Compared with healthy volunteers, plasma HMGB1 was markedly elevated in trauma patients within 1 h of injury (median, 57.76 vs. 1.77 ng/mL; healthy volunteers vs. all time periods; *P < 0.003). Peak plasma HMGB1 levels, approximately 300-fold above levels in healthy volunteers, occurred from 2 to 6 h postinjury (median, 526.18 ng/mL; †P < 0.01 vs. time periods <1 to 136 h). After peak levels, from 2 to 6 h, plasma HMGB1 remained elevated above healthy volunteers through 136 h postinjury (*P < 0.003).
Fig. 2
Fig. 2. Relationship between plasma HMGB1 and indicators of shock, ISS, and patient age
Comparison of mean HMGB1 levels with least square means (LSM) adjusted for indicators of shock (admission BD and units RBC transfused per first 24 h), or LSM adjusted for ISS and patient age was performed. No significant difference was observed when plasma HMGB1 levels were adjusted for indicators of shock or injury severity and patient age to 136 h after injury (values represent mean or LSM ± SEM).
Fig. 3
Fig. 3. Maximal postinjury plasma HMGB1 versus patient age, indicators of shock, and injury severity
Peak HMGB1 levels, from 2 to 6 hours postinjury, were evaluated independently against patient age (A), number of units of RBCs transfused per first 24 h (B), ISS (C), or admission BD (D). No clear relationship was found between peak postinjury HMGB1 levels and patient age (P = 0.65), ISS (P = 0.16), or transfusion requirement in the first 24 h (P = 0.42). A possible inverse correlation may exist between peak HMGB1 levels and BD at the time of admission. However, this trend borders on statistical significance (Spearman P value = 0.05) and requires further investigation.
Fig. 4
Fig. 4. Plasma HMGB1 levels trend higher in patients requiring longer ICU stays
Patients requiring ICU LOS greater than 14 days had consistently higher plasma HMGB1 levels than did patients requiring ICU LOS less than or equal to 14 days. This trend was most apparent during the first 24 h after injury; however, in this small study population, it did not reach statistical significance (mixed model, 0.499) and requires further investigation.
Fig. 5
Fig. 5. Concentrations of HMGB1 in stored packed RBCs are dependent on the duration of storage and whether the blood products underwent leukoreduction
Plasma HMGB1 was assayed for in both LR and NLR blood samples, from five healthy donors, at D1 and D42 after storage. High-mobility group box 1 concentration increased in NLR samples approximately 1.7-fold with 42 days of storage (15.4 ± 2.3 ng/mL D1 NLR vs. 27.3 ± 1.6 ng/mL D42 NLR; mean ± SEM, *P < 0.001 vs. D1 NLR). Leukoreduction attenuated HMGB1 levels by approximately 55% versus D1 NLR blood (†P < 0.01 vs. D1 and D42 LR RBCs), and by approximately 75% versus D42 NLR blood (*P < 0.001 vs. D1 and D42 LR RBCs). Attenuation of HMGB1 levels was durable for 42 days of storage, with no difference observed in levels between D1 LR and D42 LR RBCs.
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