title: Upregulation and Mitochondrial Sequestration of Hemoglobin Occur in Circulating Leukocytes during Critical Illness, Conferring a Cytoprotective Phenotype.
abstract: The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extra-cellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of H2S. Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCsin vitro. Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Attila
authors: A
authors: Brunyanszki
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Katalin
authors: K
authors: Erdelyi
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Shriners Hospital for Children, Galveston, Texas, United States of America.
authors: Bartosz
authors: B
authors: Szczesny
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Gabor
authors: G
authors: Olah
authors: Division of Infectious Diseases, Department of Medicine, Hospital Sao Paulo, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
authors: Reinaldo
authors: R
authors: Salomao
authors: Shriners Hospital for Children, Galveston, Texas, United States of America.|Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: David N
authors: DN
authors: Herndon
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Shriners Hospital for Children, Galveston, Texas, United States of America.
authors: Csaba
authors: C
authors: Szabo