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Trauma-induced heme release increases susceptibility to bacterial infection
Ghee Rye Lee, … , Carl J. Hauser, Leo E. Otterbein
Ghee Rye Lee, … , Carl J. Hauser, Leo E. Otterbein
Published September 14, 2021
Citation Information: JCI Insight. 2021;6(20):e150813. https://doi.org/10.1172/jci.insight.150813.
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Research Article Infectious disease Inflammation

Trauma-induced heme release increases susceptibility to bacterial infection

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Abstract

Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms, however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a potentially novel murine model in which a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show > 50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Finally, day 1 trauma patients (n = 9) showed similar elevations in free heme compared with that seen after murine liver injury, and circulating PMN showed similar TLR2 reduction compared with volunteers (n = 6). These findings correlate to high infection rates.

Authors

Ghee Rye Lee, David Gallo, Rodrigo W. Alves de Souza, Shilpa Tiwari-Heckler, Eva Csizmadia, James D. Harbison, Sidharth Shankar, Valerie Banner-Goodspeed, Michael B. Yaffe, Maria Serena Longhi, Carl J. Hauser, Leo E. Otterbein

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Figure 3

Liver crush injury does not impair PMN migration to the sites of bacterial infection.

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Liver crush injury does not impair PMN migration to the sites of bacteri...
(A) Frequency of CD11b+Ly6G+ neutrophils (PMN) in the blood 4 hours after liver crush injury (n = 6/group). (B) Absolute number of PMN in 1 mL of BALF at the baseline (n = 5), 4 hours after liver crush injury alone (n = 5), 24 hours after lung infection with and without liver crush injury (n = 20/group). (C and D) Frequency of PMN in the blood (n = 13–21/group) and the BM (n = 10–15/group), 24 hours after infection with and without liver crush injury. (E) Fold change of Ly6G MFI in PMN in BAL after lung infection with and without liver crush injury (n = 12/group). (F) A representative flow cytometry analysis image showing the MFI of Ly6G in PMN in BAL (left, infection only; right, trauma + infection). (G and H) Fold change of Ly6G MFI in PMN in the blood (n = 11–14/group) and the BM (n = 8–9/group) 24 hours after infection, with and without liver crush injury. (I–K) Levels of KC, IP-10, and MIP-1α in the BALF at the baseline (n = 3), 24 hours after infection with and without liver crush injury (n = 4–5/group). All data are presented as mean ± SEM. Statistical analyses for A, E, G, and H were performed by unpaired 2-tailed Student’s t test. All other P values were calculated by 1-way ANOVA with post hoc Tukey’s test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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