title: Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion.
abstract: After an ischemic episode, reperfusion causes profound oxidative stress in the vasculature of the afflicted tissue/organ. The dysregulated accumulation of reactive oxygen species (ROS), such as superoxide, has been closely linked to the production and release of proinflammatory mediators, a profound increase in adhesion molecule expression by the vascular endothelium, and infiltration of neutrophils during ischemia-reperfusion (I/R). Superoxide dismutase (SOD) has been shown to protect tissues and organs against I/R-induced injury; however, the drug had to be continuously perfused or kidneys had to be occluded to prevent clearance. We used intravital microscopy, a system that allowed us to visualize neutrophil-endothelial interactions within the mesenteric postcapillary venules of cats subjected to I/R and tested the hypothesis that I/R-induced neutrophil recruitment was inhibited by treatment with SOD2/3. SOD2/3 is a chimeric fusion gene product that contains the mature SOD2 as well as the COOH-terminal "tail" of SOD3 and, unlike the three naturally occurring SODs (SOD1, SOD2, and SOD3), which bear a net negative charge at pH 7.4, SOD2/3 is positively charged and physiologically stable. Our results suggest that not only does SOD2/3 have a much greater efficacy in vivo than the native human SOD2, but its administration prevents I/R-induced neutrophil-endothelial cell interactions and microvascular dysfunction. Moreover, our data support the hypothesis that reactive oxidants mediate I/R-induced injury and that the chimeric recombinant SOD2/3 has the potential to be a therapeutic agent against this debilitating illness.
authors.affiliation: Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.forename: Derrice
authors.initials: D
authors.lastname: Knight
authors.forename: Daniel
authors.initials: D
authors.lastname: Hernandez-Saavedra
authors.forename: Joe M
authors.initials: JM
authors.lastname: McCord
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000494:pharmacology*; D000099156:Superoxide Dismutase 2
chemical_list: D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C441642:SOD3 protein, human