title: Extracellular Hb enhances cardiac toxicity in endotoxemic guinea pigs: protective role of haptoglobin.
abstract: Endotoxemia plays a major causative role in the myocardial injury and dysfunction associated with sepsis. Extracellular hemoglobin (Hb) has been shown to enhance the pathophysiology of endotoxemia. In the present study, we examined the myocardial pathophysiology in guinea pigs infused with lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, and purified Hb. We also examined whether the administration of the Hb scavenger haptoglobin (Hp) could protect against the effects observed. Here, we show that Hb infusion following LPS administration, but not either insult alone, increased myocardial iron deposition, heme oxygenase-1 expression, phagocyte activation and infiltration, as well as oxidative DNA damage and apoptosis assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunostaining, respectively. Co-administration of Hp significantly attenuated the myocardial events induced by the combination of LPS and Hb. These findings may have relevant therapeutic implications for the management of sepsis during concomitant disease or clinical interventions associated with the increased co-exposures to LPS and Hb, such as trauma, surgery or massive blood transfusions.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. jin.baek@fda.hhs.gov.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. xiaoyuan.zhang@fda.hhs.gov.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. matthew.williams@fda.hhs.gov.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Williams
authors.affiliation: Division of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland. dominik.schaer@usz.ch.
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. paul.buehler@fda.hhs.gov.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. felice.dagnillo@fda.hhs.gov.
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism; D006168:Guinea Pigs; D006242:Haptoglobins / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000633:toxicity*; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis; D018805:Sepsis / Q000209:etiology / Q000378:metabolism
chemical_list: C485359:HP protein, human; D006242:Haptoglobins; D006454:Hemoglobins; D008070:Lipopolysaccharides; D007501:Iron; D051547:Heme Oxygenase-1