title: Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo.
abstract: Pro-inflammatory activation of vascular endothelium is implicated in pathogenesis of severe conditions including stroke, infarction and sepsis. We have recently reported that superoxide dismutase (SOD) conjugated with antibodies (Ab/SOD) that provide targeted delivery into endothelial endosomes mitigates inflammatory endothelial activation by cytokines and agonists of Toll-like receptors (TLR). The goal of this study was to appraise potential utility and define the mechanism of this effect. Ab/SOD, but not non-targeted SOD injected in mice alleviated endotoxin-induced leukocyte adhesion in the cerebral vasculature and protected brain from ischemia-reperfusion injury. Transfection of endothelial cells with SOD, but not catalase inhibited NFκB signaling and expression of Vascular Cell Adhesion Molecule-1 induced by both cytokines and TLR agonists. These results affirmed that Ab/SOD-quenched superoxide anion produced by endothelial cells in response to proinflammatory agents mediates NFκB activation. Furthermore, Ab/SOD potentiates anti-inflammatory effect of NO donors in endothelial cells in vitro, as well as in the endotoxin-challenged mice. These results demonstrate the central role of intracellular superoxide as a mediator of pro-inflammatory activation of endothelium and support the notion of utility of targeted interception of this signaling pathway for management of acute vascular inflammation.
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Samira
authors.initials: S
authors.lastname: Tliba
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Servio H
authors.initials: SH
authors.lastname: Ramirez
authors.forename: Holly
authors.initials: H
authors.lastname: Dykstra
authors.forename: Yuri
authors.initials: Y
authors.lastname: Persidsky
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000737:chemistry; D013481:Superoxides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014657:Vasculitis / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020011:Protective Agents; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D013482:Superoxide Dismutase