title: Delineating the relationships among the formation of reactive oxygen species, cell membrane instability and innate autoimmunity in intestinal reperfusion injury.
abstract: Acute intestinal ischemia is a medical emergency with a high mortality rate, attesting to the need for a better understanding of its pathogenesis and the development of effective therapies. The goal of this study was to delineate the relationships among intracellular and extracellular events in intestinal ischemia/reperfusion (I/R) injury, particularly the formation of reactive oxygen species (ROS), cell membrane instability associated with lipid peroxidation and the innate autoimmune response mediated by natural IgM and complement. A murine model of natural IgM-mediated intestinal I/R was used. Mice overexpressing anti-oxidant enzyme SOD1 were found to have significantly reduced intestinal tissue damage and complete blockage of IgM-mediated complement activation compared with WT controls. To determine if cell membrane instability was an event intermediate between ROS formation and natural IgM-mediated innate autoimmune response, the cell membrane stabilizer (trehalose) was administered to WT mice prior to the induction of intestinal ischemia. Treatment with trehalose significantly protected animals from I/R injury and inhibited IgM-mediated complement activation although it did not prevent membrane lipid peroxidation. These data indicate that in normal mice subjected to I/R injury, intracellular ROS formation is an event upstream of the lipid peroxidation which results in cell membrane instability. The membrane instability leads to an innate autoimmune response by natural IgM and complement. Trehalose, a nontoxic disaccharide tolerated well by animals and humans, has promise as a protective agent for patients with medical conditions related to acute intestinal ischemia.
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States.
authors.forename: Haekyung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Ko
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Biomedical Sciences, Long Island University, Brookville, NY 11548, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Lai
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Biomedical Sciences, Long Island University, Brookville, NY 11548, United States.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Chemical and Biomolecular Engineering, NYU-Polytechnic Institute, Brooklyn, NY 11201, United States.
authors.forename: Javi
authors.initials: J
authors.lastname: Balroop
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States.
authors.forename: Zerin
authors.initials: Z
authors.lastname: Kashem
authors.affiliation: Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States. Electronic address: ming.zhang@downstate.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000293:injuries; D007511:Ischemia / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D065666:Mesenteric Ischemia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014199:Trehalose / Q000008:administration & dosage; D014652:Vascular Diseases / Q000188:drug therapy / Q000276:immunology*
chemical_list: D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D014199:Trehalose; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Cell membrane instability; Complement; Natural IgM; Reactive oxygen species; Reperfusion injury; Trehalose