Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo

• Published in: PloS one 2013-10, Vol.8 (10), p.e77002
• Main Authors: Shuvaev, Vladimir V, Han, Jingyan, Tliba, Samira, Arguiri, Evguenia, Christofidou-Solomidou, Melpo, Ramirez, Servio H, Dykstra, Holly, Persidsky, Yuri, Atochin, Dmitriy N, Huang, Paul L, Muzykantov, Vladimir R
• Format: Article
• Language: English
• Subjects: Activation; Adhesion; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - administration & dosage; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Brain; Brain injury; Catalase; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cerebral infarction; Cytokines; Cytokines - biosynthesis; Cytokines - pharmacology; Disease Models, Animal; Drug Synergism; Endosomes; Endothelial cells; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Immune system; Infarction; Inflammation; Interception; Intracellular Space - metabolism; Ischemia; Leukocytes; Male; Mice; Molecular chains; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide Donors - pharmacology; Pathogenesis; Pathology; Platelet Endothelial Cell Adhesion Molecule-1 - immunology; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Protective Agents - pharmacology; Proteins; Reactive Oxygen Species - metabolism; Receptors; Reperfusion; Sepsis; Signal transduction; Signal Transduction - drug effects; Signaling; Superoxide dismutase; Superoxide Dismutase - administration & dosage; Superoxide Dismutase - chemistry; Superoxides; Superoxides - metabolism; Synergism; Toll-like receptors; Transfection; Tumor necrosis factor-TNF; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - metabolism; Vasculitis - drug therapy; Vasculitis - metabolism; Vasculitis - prevention & control
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077002

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.