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PubMed: 29522519

Title
Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study.
Journal
PLoS medicine
Volume
15
Issue
None
Pages
e1002522
Date
2018-03-01
Authors
Patel RP | Marques MB | Oh JY | Wagener BM | Brandon AP | Creighton J | Dull RO | Evans CA | Honavar J | Hu PJ | Kerby JD | Morgan C | Pittet JF | Richter JR | Stephens SW

Evidence 7c01dd55fb
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Fig 2 shows that free hemoglobin and free heme were higher 4 h after resuscitation with stored RBCs compared to fresh RBCs (n = 3±7 as indicated); NTBI level was also higher, but this difference did not reach statistical significance (p = 0.07).

a(CHEBI:"iron(2+)") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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a(CHEBI:heme) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation p(MGI:"Hbb-b1") View Subject | View Object

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p(MGI:"Hbb-b1") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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Evidence 5692d292ee
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Furthermore, free heme also induced extracellular release of HMGB1 from RMVECs compared to vehicle control (Fig 5B).

a(CHEBI:heme) positiveCorrelation p(MGI:Hmgb1) View Subject | View Object

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p(MGI:Hmgb1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence b893c6fbe3
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Consistent with our previous studies [25,36], free oxyHb, metHb, and heme levels were increased after 14 d of RBC storage, being 930 ± 125 μM, 40.3 ± 8.8 μM, and 168 ± 44.7 μM, respectively (mean ± SEM, n = 7).

a(CHEBI:heme) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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a(CHEBI:methemoglobin) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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a(CHEBI:oxyhemoglobin) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:oxyhemoglobin) View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:methemoglobin) View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence cfdb5c8dfd
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These data indicate that the increased severity of bacterial lung injury secondary to massive resuscitation with stored RBCs is heme-dependent.

a(CHEBI:heme) positiveCorrelation path(MESH:"Lung Injury") View Subject | View Object

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path(MESH:"Lung Injury") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence e3e3f3b3e0
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In summary, these results indicate that heme from resuscitation with stored RBCs increases extracellular release of HMGB1, which inhibits macrophage phagocytosis of P. aeruginosa, leading to increased mortality.

a(CHEBI:heme) positiveCorrelation p(MGI:Hmgb1) View Subject | View Object

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p(MGI:Hmgb1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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p(MGI:Hmgb1) decreases bp(GO:phagocytosis) View Subject | View Object

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macrophage
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Evidence e4b4f9deaf
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However, mortality significantly increased in mice resuscitated with stored RBCs (median survival 8 h, n = 9), with all mice dying within 20 h of PAK instillation (Fig 1C).

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Evidence 8d9618ee05
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Pulmonary edema approximately doubled (Fig 1D), and lung bacterial CFUs significantly increased (Fig 1E) in mice resuscitated with stored RBCs compared to those that received fresh RBCs.

a(HM:"stored erythrocytes") positiveCorrelation path(MESH:"Pulmonary Edema") View Subject | View Object

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a(HM:"stored erythrocytes") positiveCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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bp(MESH:"Bacterial Load") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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path(MESH:"Pulmonary Edema") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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Evidence 1bc72a5690
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TH and resuscitation with stored compared to fresh RBCs not only caused increased mortality but also significantly increased the severity of pulmonary edema induced by P. aeruginosa pneumonia (Fig 1D).

a(HM:"stored erythrocytes") positiveCorrelation path(MESH:"Pulmonary Edema") View Subject | View Object

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path(MESH:"Pulmonary Edema") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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Evidence f8ed9916a1
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Fig 5A shows that extracellular serum levels of HMGB1 were approximately 5-fold higher in mice (n = 3) resuscitated with stored RBCs compared to mice resuscitated fresh RBCs.

a(HM:"stored erythrocytes") positiveCorrelation p(MGI:Hmgb1) View Subject | View Object

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p(MGI:Hmgb1) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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Evidence abeea188ee
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Our findings using a mouse model of trauma and hemorrhagic shock with stored blood transfusion and subsequent PAK instillation demonstrate that transfusion with older stored RBCs increases the severity of bacterial pneumonia.

a(HM:"stored erythrocytes") positiveCorrelation path(MESH:Pneumonia) View Subject | View Object

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Cell Ontology (CL)
macrophage
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path(MESH:Pneumonia) positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

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macrophage
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Evidence db3a0b9198
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Hemopexin improved post-pneumonia survival in mice that underwent massive resuscitation with stored RBCs (Fig 3A).

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path(MESH:Pneumonia) negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Evidence 681251a7f9
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These data demonstrate that TLR4 signaling plays a role in heme-induced exacerbation of lung bacterial infection secondary to TH followed by massive resuscitation with stored RBCs.

act(p(MGI:Tlr4)) negativeCorrelation path(MESH:"Lung Injury") View Subject | View Object

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path(MESH:"Lung Injury") negativeCorrelation act(p(MGI:Tlr4)) View Subject | View Object

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