Critical Care Medicine  |   July 2017
Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis
Author Notes
  • 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.).
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    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication February 21, 2016. Accepted for publication March 14, 2017.
    Submitted for publication February 21, 2016. Accepted for publication March 14, 2017.×
  • Address correspondence to Dr. Bagchi: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, White 434B, Boston, Massachusetts 02114. abagchi@mgh.harvard.edu.Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Endocrine and Metabolic Systems / Gastrointestinal and Hepatic Systems
Critical Care Medicine   |   July 2017
Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis
Anesthesiology 7 2017, Vol.127, 121-135. doi:10.1097/ALN.0000000000001653
Anesthesiology 7 2017, Vol.127, 121-135. doi:10.1097/ALN.0000000000001653
Abstract

Background: Perioperative 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.

Methods: Murine 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.

Results: Iron 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.

Conclusions: Acute 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.