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

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 1

Liver crush injury decreases bacterial clearance in the lung.

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Liver crush injury decreases bacterial clearance in the lung. (A) Repres...
(A) Representative images of the naive left liver lobe and 1, 4, and 24 hours after injury (5 sections/tissue, n = 3/group). Scale bar: 100 μm. Original magnification, ×200. Close-up images of PMN are shown. (B) Levels of alanine aminotransferase (ALT) in plasma before (n = 3) and after liver crush injury (n = 4-11/group). (C) Posttraumatic pneumonia model: liver crush injury is performed in the left liver lobe, and 4 hours later, mice are challenged with 1 × 106 to 1 × 107 CFU of S. aureus in the lung. Twenty-four hours after infection, cells and tissues were harvested for further analysis. (D and E) Fold change of S. aureus CFU in bronchoalveolar fluid (BALF) after infection only, after infection with laparotomy or liver crush injury (n = 10–19/group) and in lung tissues (n = 4–6/group). (F) S. aureus CFU in 50 μL of plasma in the post-traumatic pneumonia model (n = 6–10/group). (G) Protein levels in the BALF at the baseline (n = 3), 24 hours after infection with and without liver crush injury (n = 8/group). (H) Survival curve of mice with and without liver crush and with 1 × 106 to 1 × 107 or 1 × 107 to 1 × 108 CFU of S. aureus (n = 4–5/group). (I) Fold change of S. aureus CFU in BALF after infection only or with liver crush injury performed 24 hours prior to the infection (n = 18–20/group). (J) Fold change of E. coli CFU in BALF collected 24 hours after infection, with and without liver crush injury performed 4 hours prior to the infection (n = 4–5/group). All data are presented as mean ± SEM. Statistical analyses for I and J 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.