title: Vasculotoxic and Proinflammatory Effects of Plasma Heme: Cell Signaling and Cytoprotective Responses.
abstract: The proinfammatory vasculotoxic effects of intravascular hemolysis are modulated by plasma hemoglobin and heme clearance via the haptoglobin/CD163 system and the hemopexin/CD91 system, respectively, and detoxification through the heme oxygenase/ferritin system. However, sudden or excessive hemolysis can overwhelm these protective systems leading to heme interacting with cells of the vasculature. Heme presents a damage-associated molecular pattern to the innate immune system. Heme is an extracellular inflammatory signaling molecule with strict binding specificity for TLR4 on monocyte/macrophages, endothelial, and other cells. The resulting TLR4 signaling cascade rapidly leads to intracellular oxidative stress and an inflammatory response. Heme also induces a cytoprotective response that includes Nrf2 responsive genes such as heme oxygenase-1, ferritin, haptoglobin, hemopexin, and other antioxidant response genes. It is the balance between the pro-inflammatory/vasculotoxic effects of plasma hemoglobin/heme and the cytoprotective responses that ultimately determines the pathophysiologic outcome in patients.
authors.affiliation: Division of Hematology, Oncology and Transplantation, Vascular Biology Center, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.affiliation: Division of Hematology, Oncology and Transplantation, Vascular Biology Center, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti