• Konrad Hoeft, Donald B Bloch, Jan A Graw, Rajeev Malhotra, Fumito Ichinose, and Aranya Bagchi.
• From the Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine (K.H., D.B.B., J.A.G., F.I., A.B.), Division of Rheumatology, Allergy and Immunology, Department of Medicine (D.B.B.), and Division of Cardiovascular Medicine, Department of Medicine (R.M.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Anesthesiology, University Hospital of the RWTH Aachen, Aachen, Germany (K.H.).
• Anesthesiology. 2017 Jul 1; 127 (1): 121-135.

BackgroundPerioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels.MethodsMurine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria.ResultsIron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria.ConclusionsAcute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients.

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