Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood

Baek, Jin Hyen; Yalamanoglu, Ayla; Gao, Yamei; Guenster, Ricardo; Spahn, Donat R.; Schaer, Dominik J.; Buehler, Paul W.

doi:10.1172/jci.insight.93577

Cited by 19 publications

(21 citation statements)

References 35 publications

(49 reference statements)

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“…In subsequent reactions, metHb or metHb‐derived heme participates in redox chain reactions that lead to the accumulation of modified lipids and proteins, as well as to heme degradation and to the release of free iron . Ultimately, these processes can result in oxidative tissue injury, which may be accompanied by a tissue regenerative response or by secondary inflammation . The third process suggests that free heme could be recognized by innate immunity receptors as an endogenous DAMP, which may directly activate inflammatory signaling pathways in leukocytes and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…19,25 Ultimately, these processes can result in oxidative tissue injury, which may be accompanied by a tissue regenerative response or by secondary inflammation. 26 The third process suggests that free heme could be recognized by innate immunity receptors as an endogenous DAMP, which may directly activate inflammatory signaling pathways in leukocytes and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Revisiting the putative role of heme as a trigger of inflammation

Vallelian

Schaer

Deuel

et al. 2018

Pharmacology Res & Perspec

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Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell‐free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb‐based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein‐binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein‐free heme under in vivo equilibrium conditions. We demonstrate that the capacity of heme to activate human neutrophil granulocytes strictly depends on the availability of non protein‐associated heme. In human endothelial cells as well as in mouse macrophage cell cultures and in mouse models of local and systemic heme exposure, protein‐associated heme or Hb do not induce inflammatory gene expression over a broad range of exposure conditions. Only experiments in protein‐free culture medium demonstrated a weak capacity of heme‐solutions to induce toll‐like receptor‐(TLR4) dependent TNF‐alpha expression in macrophages. Our data suggests that the equilibrium‐state of free and protein‐associated heme critically determines the proinflammatory capacity of the metallo‐porphyrin. Based on these data it appears unlikely that inflammation‐promoting equilibrium conditions could ever occur in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Revisiting the putative role of heme as a trigger of inflammation

Vallelian

Schaer

Deuel

et al. 2018

Pharmacology Res & Perspec

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“…Direct colorimetric NTBI detection of plasma was performed according to a chromogenic method described previously …”

Section: Methodsmentioning

confidence: 99%

“…Direct colorimetric NTBI detection of plasma was performed according to a chromogenic method described previously. 36 For tissue iron, spleen, liver, and kidney tissue (100 mg) were homogenized in double deionized H 2 O at 1:10 wt/vol. Homogenates were mixed with 500 μL of an acid preparation containing 1 mM HCl and 10% trichloroacetic acid and incubated at 50°C for 1 hour with intermittent shaking, according to previously described methods.…”

Section: Plasma and Tissue Iron Measurementsmentioning

confidence: 99%

Ferroportin inhibition attenuates plasma iron, oxidant stress, and renal injury following red blood cell transfusion in guinea pigs

et al. 2020

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BACKGROUND Red blood cell (RBC) transfusions result in the sequestration and metabolism of storage‐damaged RBCs within the spleen and liver. These events are followed by increased plasma iron concentrations that can contribute to oxidant stress and cellular injury. We hypothesized that administration of a ferroportin inhibitor (FPN‐INH) immediately after acute RBC exchange transfusion could attenuate posttransfusion circulatory compartment iron exposure, by retaining iron in spleen and hepatic macrophages. STUDY DESIGN AND METHODS Donor guinea pig blood was leukoreduced, and RBCs were preserved at 4°C. Recipient guinea pigs (n = 5/group) were exchange transfused with donor RBCs after refrigerator preservation and dosed intravenously with a small‐molecule FPN‐INH. Groups included transfusion with vehicle (saline), 5 mg/kg or 25 mg/kg FPN‐INH. A time course of RBC morphology, plasma non–transferrin‐bound iron (NTBI) and plasma hemoglobin (Hb) were evaluated. End‐study spleen, liver, and kidney organ iron levels, as well as renal tissue oxidation and injury, were measured acutely (24‐hr after transfusion). RESULTS RBC transfusion increased plasma NTBI, with maximal concentrations occurring 8 hours after transfusion. Posttransfusion iron accumulation resulted in tubule oxidation and acute kidney injury. FPN inhibition increased spleen and liver parenchymal/macrophage iron accumulation, but attenuated plasma NTBI, and subsequent renal tissue oxidation/injury. CONCLUSION In situations of acute RBC transfusion, minimizing circulatory NTBI exposure by FPN inhibition may attenuate organ‐specific adverse consequences of iron exposure.

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“…The RBC storage lesions are characterized by altered RBC morphology, rheologic changes, metabolic derangements, changes in oxygen affinity, changes in osmotic regulation, and changes in the ability to vasoregulate . In addition, RBC hemolysis (both during storage and after transfusion) can lead to reduced pH, increased lactate and other metabolic wastes, and release of microparticles as well as accumulation of cell‐free hemoglobin (Hb), heme, and iron . Iron content can be in the form of transferrin‐bound iron, non–transferrin‐bound iron (NTBI), or labile plasma iron.…”

Section: Proposed Mechanismsmentioning

confidence: 99%

Mechanisms of red blood cell transfusion‐related immunomodulation

et al. 2018

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Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions.

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Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood

Cited by 19 publications

References 35 publications

Revisiting the putative role of heme as a trigger of inflammation

Revisiting the putative role of heme as a trigger of inflammation

Ferroportin inhibition attenuates plasma iron, oxidant stress, and renal injury following red blood cell transfusion in guinea pigs

Mechanisms of red blood cell transfusion‐related immunomodulation

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