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Open Access

Protective/reparative cytokines are suppressed at high injury severity in human trauma

Jinman Cai, Todd McKinley, Isabel Billiar, Mazen S Zenati, Greg Gaski, Yoram Vodovotz, Danielle S Gruen, Timothy R Billiar, Rami A Namas
DOI: 10.1136/tsaco-2020-000619 Published 2 March 2021
Jinman Cai
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Todd McKinley
2Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Isabel Billiar
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Mazen S Zenati
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Greg Gaski
3Department of Orthopedic Surgery, Inova Fairfax Medical Campus, Falls Church, Virginia, USA
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Yoram Vodovotz
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
4Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
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Danielle S Gruen
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • ORCID record for Danielle S Gruen
Timothy R Billiar
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
4Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
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Rami A Namas
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
4Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
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  • Figure 1
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    Figure 1

    Linear regression of plasma inflammatory biomarkers and ISS within the first 24 hours postinjury in the overall TD-1 (n=472) and TD-2 (n=89) survivor cohort. (A) IL-9, (B) IL-21, (C) IL-22, (D) IL-23 and (E) IL-17E/25. IL, interleukin; ISS, Injury Severity Score; TD-1, trauma database-1; TD-2, trauma database-2.

  • Figure 2
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    Figure 2

    Time course analysis of inflammation biomarkers in the mild, moderate and severe ISS-based groups from time of injury up to 7 days in TD-1 (University of Pittsburgh). Circulating levels of inflammatory mediators in the mild (n=180), moderate (n=170) and severe (n=122) ISS groups assessed in serial plasma samples obtained at the indicated time points. Time courses of (A) IL-9, (B) IL-21, (C) IL-22, (D) IL-23 and (E) IL-17E/25. Values are mean±SEM. *Mild versus severe, #moderate versus severe; p<0.05 by two-way analysis of variance. IL, interleukin; ISS, Injury Severity Score; TD-1, trauma database-1.

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    Figure 3

    Time course analysis of inflammation biomarkers in the mild, moderate and severe ISS-based groups from time of injury up to 3 days in TD-2 (Indiana university). Mean circulating levels of inflammatory mediators in the mild (n=12), moderate (n=21) and severe (n=56) ISS groups assessed in serial plasma samples obtained at the indicated time points. Time courses of (A) IL-9, (B) IL-21, (C) IL-22, (D) IL-23 and (E) IL-17E/25. Values are mean±SEM. *Mild versus severe, #moderate versus severe; p<0.05 by two-way analysis of variance. IL, interleukin; ISS, Injury Severity Score; TD-2, trauma database-2.

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    Figure 4

    Schematic that depicts the relationship between injury severity and the release of cytokine immune modulators after injury. Proinflammatory mediators, which are known to contribute to excess inflammation and tissue injury after trauma, continue to increase as injury severity increases. In contrast, a set of protective/reparative cytokines increase at lower and more survivable levels of injury but then become suppressed above a certain threshold of injury severity.

Tables

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  • Table 1

    Overall demographics, trauma scores, mechanism of injury, clinical outcomes and disposition of the three injury severity groups segregated based on their ISS for the two separate databases used in the study, including TD-1 (University of Pittsburgh) and TD-2 (Indiana University)

    ISS-based groupsTD-1 (University of Pittsburgh)TD-2 (Indiana University)
    Mild
    (1–15) n=180
    Moderate
    (16–24) n=170
    Severe
    (≥25) n=122
    P valueMild
    (1–15) n=12
    Moderate
    (16–24) n=21
    Severe
    (≥25) n=56
    P value
    Demographics
     Age (year)52 (37.8–64.3)52 (35–64)37 (26.0–51.8)<0.001*†34 (26.5–49.8)43 (33.5–49.0)34 (22.5–45.0)0.05
     Sex, M/FM=125 F=55M=118 F=52M=87 F=350.93M=12 F=0M=15 F=6M=41 F=150.12
    Trauma scores
     ISS10 (9–13)19 (17–21)34 (28–38)<0.001*†‡13.5 (9–14)21 (17–22)36 (30–43)<0.001*†
     Marshall Multiple Organ Dysfunction Score, average days1–70.4 (0–1.3)0.6 (0–2)1.4 (0.4–2.8)<0.001*†1.4 (0.8–3.5)2.5 (1.0–4.8)4.3 (2.3–6.4)0.003*
    Abbreviated Injury Scale 2005–update 2008 version
     Head and neck0 (0–2)0 (0–3)3 (0–4)<0.001*†0 (0–1)1 (0–3)2 (0–3)0.037*
     Face0 (0–0)0 (0–0)0 (0–2)0.016*1 (1–2)1 (0–1)1 (0–1)0.4
     Chest1 (0–3)3 (2–3)3 (2-4)<0.001*†‡2 (2–3)2 (2–3)2 (1–4)0.7
     Abdomen0 (0–2)1 (0–2)2 (0–4)<0.001*†‡1 (0–2)2 (1–3)2 (0–4)0.066
     Extremities0 (0–2)2 (0–2)3 (2–3)<0.001*†‡0 (0–1)1 (0–1)1 (0–2)0.2
     External1 (0–1)1 (0–1)1 (0–1)0.590 (0–1)2 (0–2)4 (1.75–4.0)<0.001*†
    Mechanism of injury
     Motor vehicle crashes, n (%)100 (55.6)98 (57.7)71 (58.2)0.888 (66.7)11 (52.4)37 (66.1)0.88
     Motorcycle, n (%)16 (8.9)14 (8.2)23 (18.9)0.0082 (16.7)2 (9.5)4 (7.1)0.64
     Fall, n (%)45 (25)39 (22.9)18 (14.8)0.090 (0)2 (9.5)3 (5.4)0.81
     Other, n (%)19 (10.6)19 (11.2)10 (8.2)0.692 (16.7)6 (28.6)12 (21.4)0.80
    Clinical outcomes
    Intensive care unit LOS (days)2 (1–4)4 (2–7)10 (4–17)<0.001*†‡3 (2.3–4.8)5 (3.0–12.5)9 (4–17)<0.001*
    Total hospital LOS (days)6.5 (4.0–11.3)9 (6–15)16 (10–27)<0.001*†‡5 (4–8)15 (9.0–21.5)17 (9.3–25.8)<0.001*‡
    Mechanical ventilation (days)0 (0–1)0 (0–2)4.5 (1.0–12.8)<0.001*†2 (2.0–3.8)3 (0–9.5)5 (2–14)0.082
    Nosocomial infection, n (%)29 (16.1)41 (24.1)57 (46.7)<0.0011 (8.3)7 (33.3)26 (46.4)0.032
    Disposition
    Home, n (%)112 (62.2)75 (44.1)43 (35.2)<0.0016 (50.0)8 (38.1)17 (30.3)0.66
    Other facilities, n (%)68 (37.8)95 (55.9)79 (64.8)<0.0016 (50.0)13 (61.2)39 (69.6)0.82
    Physiological and biochemical parameters
    Shock index (heart rate/systolic blood pressure)0.7 (0.6–0.9)0.7 (0.6–0.9)0.9 (0.7–1.2)<0.001*†0.8 (0.6–0.9)0.7 (0.6–0.8)1.0 (0.7–1.4)0.009
    Systolic blood pressure (mm Hg)130 (112–148)130 (112–148)118 (95–136)<0.001*†125 (110–136)139 (124–142)110 (92–128)0.001
    Base deficit (mEq/L)4 (7–1)4 (6–3)6 (9–3)0.001*†3 (6.5–2.0)4 (6.5–3.0)5.5 (8–3)0.17
    Lactate (mmol/L)2.3 (1.3–3.3)2.4 (1.4–3.5)3.2 (2.1–4.4)<0.001*†2.1 (1.2–4.1)2.9 (2.5–4.5)4.2 (2.9–5.6)0.31
    Creatinine (mg/dL)1 (0.8–1.1)1 (0.8–1.2)1 (0.9–1.3)0.0991.1 (0.9–1.2)1 (0.9–1.1)1.1 (0.9–1.3)0.45
    White blood cell count (×103/µL)13.4 (10.6–16.9)14.0 (10.5–18.9)16.0 (11.8–21.3)<0.001*15.8 (9.3–17.6)16.8 (14.0–19.9)18.2 (12.5–26)0.13
    International normalized ratio1.1 (1.1–1.2)1.1 (1.1–1.2)1.2 (1.1–1.3)<0.001*†1.1 (1.0–1.1)1.1 (1.1–1.2)1.2 (1.1–1.3)0.005*†
    • The mild ISS group (ISS: 1–15, n=180 and n=12), moderate ISS group (ISS: 16–24, n=170 and n=21) and severe ISS group (ISS: ≥25, n=122 and n=56) in TD-1 and TD-2, respectively.

    • Values are expressed as median (IQR).

    • P<0.05 by one-way analysis of variance.

    • *Mild versus severe.

    • †Moderate versus severe.

    • ‡Mild versus moderate.

    • ISS, Injury Severity Score; LOS, length of stay; TD-1, trauma database-1 ; TD-2, trauma database-2 .

Supplementary Materials

  • Figures
  • Tables
  • Additional Files
  • Supplementary data

    [tsaco-2020-000619supp001.pdf]

  • Supplementary data

    [tsaco-2020-000619supp002.pdf]

  • Supplementary data

    [tsaco-2020-000619supp003.pdf]

  • Supplementary data

    [tsaco-2020-000619supp004.pdf]

Additional Files

  • Figures
  • Tables
  • Supplementary Materials
  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    • Data supplement 1
    • Data supplement 2
    • Data supplement 3
    • Data supplement 4
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Protective/reparative cytokines are suppressed at high injury severity in human trauma
Jinman Cai, Todd McKinley, Isabel Billiar, Mazen S Zenati, Greg Gaski, Yoram Vodovotz, Danielle S Gruen, Timothy R Billiar, Rami A Namas
Trauma Surg Acute Care Open Mar 2021, 6 (1) e000619; DOI: 10.1136/tsaco-2020-000619

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Protective/reparative cytokines are suppressed at high injury severity in human trauma
Jinman Cai, Todd McKinley, Isabel Billiar, Mazen S Zenati, Greg Gaski, Yoram Vodovotz, Danielle S Gruen, Timothy R Billiar, Rami A Namas
Trauma Surg Acute Care Open Mar 2021, 6 (1) e000619; DOI: 10.1136/tsaco-2020-000619
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Protective/reparative cytokines are suppressed at high injury severity in human trauma
Jinman Cai, Todd McKinley, Isabel Billiar, Mazen S Zenati, Greg Gaski, Yoram Vodovotz, Danielle S Gruen, Timothy R Billiar, Rami A Namas
Trauma Surgery & Acute Care Open Mar 2021, 6 (1) e000619; DOI: 10.1136/tsaco-2020-000619
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