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Merck

Revisiting the putative role of heme as a trigger of inflammation.

Pharmacology research & perspectives (2018-04-04)
Florence Vallelian, Christian A Schaer, Jeremy W Deuel, Giada Ingoglia, Rok Humar, Paul W Buehler, Dominik J Schaer
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hemin, BioXtra, from Porcine, ≥96.0% (HPLC)
Pricing and availability is not currently available.
Sigma-Aldrich
Anti-iNOS/NOS II Antibody, NT, from rabbit, purified by affinity chromatography
Pricing and availability is not currently available.