Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo.
Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo.
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DOI：
10.1371/journal.pone.0077002
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Muzykantov VR
中科院分区：
文献类型：
--
作者：
Shuvaev VV;Han J;Tliba S;Arguiri E;Christofidou-Solomidou M;Ramirez SH;Dykstra H;Persidsky Y;Atochin DN;Huang PL;Muzykantov VR
血管内皮的促炎激活与中风、梗死和败血症等严重疾病的发病机制有关。我们最近报道了超氧化物歧化酶（SOD）与抗体（Ab/SOD）结合，提供靶向递送到内皮内体，减轻细胞因子和toll样受体激动剂（TLR）的炎症内皮活化。本研究的目的是评估潜在的效用，并确定这种效应的机制。小鼠注射Ab/SOD，而非非靶向SOD，可减轻内毒素诱导的脑血管白细胞粘附，保护脑缺血再灌注损伤。转染过氧化物歧化酶（SOD）而非过氧化氢酶（过氧化氢酶）的内皮细胞可抑制细胞因子和TLR激动剂诱导的NFκB信号传导和血管细胞粘附分子-1的表达。这些结果证实了内皮细胞响应促炎剂产生的Ab/ sod淬灭的超氧阴离子介导NFκB活化。此外，在内皮细胞和内毒素刺激小鼠中，Ab/SOD增强了NO供体的抗炎作用。这些结果证明了细胞内超氧化物作为内皮促炎激活介质的核心作用，并支持靶向阻断该信号通路用于管理急性血管炎症的概念。
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.
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影响因子：
32.4
作者：
Legler, DF;Micheau, O;Bron, C
通讯作者：
Bron, C
DOI：
10.1016/j.jconrel.2012.07.044
发表时间：
2012-09-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Manickam DS;Brynskikh AM;Kopanic JL;Sorgen PL;Klyachko NL;Batrakova EV;Bronich TK;Kabanov AV
通讯作者：
Kabanov AV
影响因子：
8.3
作者：
Atochin, DN;Murciano, JC;Muzykantov, VR
通讯作者：
Muzykantov, VR
DOI：
10.1111/j.1749-6632.2010.05607.x
发表时间：
2010-01-01
期刊：
OXIDATIVE/NITROSATIVE STRESS AND DISEASE
影响因子：
--
作者：
Laskin, Debra L.;Sunil, Vasanthi R.;Laskin, Jeffrey D.
通讯作者：
Laskin, Jeffrey D.
影响因子：
5.4
作者：
Huang, Jianlin;Lin, Zhuofeng;Gu, Jieruo
通讯作者：
Gu, Jieruo