title: Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model.
abstract: Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and granulocytes in most mammalian species. It is involved in regulation of immune responses, possesses anti-oxidant, anti-carcinogenic, anti-inflammatory properties, and provides protection against various microbial infections. In addition, lactoferrin has been implicated in protection against the development of insult-induced systemic inflammatory response syndrome (SIRS) and its progression into septic conditions in vivo. Here we show a potential mechanism by which lactoferrin lessens oxidative insult at the cellular and tissue levels after lipopolysaccharide (LPS) exposure. Lactoferrin pretreatment of cells decreased LPS-mediated oxidative insults in a dose-dependent manner. Lipopolysaccharide-induced oxidative burst was found to be of mitochondrial origin, and release of reactive oxygen species (ROS) was localized to the respiratory complex III. Importantly, lactoferrin nearly abolished LPS-induced increases in mitochondrial ROS generation and the accumulation of oxidative damage in the DNA. In vivo, pretreatment of experimental animals with lactoferrin significantly (P<0.05) lowered LPS-induced mitochondrial dysfunction as shown by both decreased release of H(2)O(2) and DNA damage in the mitochondria. In contrast, deferoxamine, an iron chelating compound, provided only partial protection in LPS-treated animals. Together, these data suggest that lactoferrin protects against oxidative insult at the mitochondrial level, and indicate a potential utility of lactoferrin in prevention and treatment of SIRS.
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston Medical School, Texas, USA.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Kruzel
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Actor
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radak
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Saavedra-Molina
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D014450:Electron Transport Complex III / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007781:Lactoferrin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D017262:Siderophores; D006861:Hydrogen Peroxide; D007781:Lactoferrin; D014450:Electron Transport Complex III; D003676:Deferoxamine