Targeted modulation of reactive oxygen species in the vascular endothelium

Shuvaev, Vladimir V.; Muzykantov, Vladimir R.

doi:10.1016/j.jconrel.2011.03.022

Cited by 49 publications

(50 citation statements)

References 122 publications

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“…However, ROS are also produced in intracellular compartments of the endothelial cells lining blood vessels in response to inflammatory mediators and other damage-associated signals [10, 11]. In particular, ROS produced in the endosomes activate the NF-κB-mediated signaling pathway leading to endothelial activation and dysfunction, as manifested by expression of inducible adhesion molecules (e.g., VCAM-1) [12], enhanced permeability [13], and loss of the anti-thrombotic phenotype [14], aggravating tissue injury and propagating the vicious cycle of vascular oxidative stress and inflammation [15]. …”

Section: Introductionmentioning

confidence: 99%

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Howard

Greineder

Hood

et al. 2014

Journal of Controlled Release

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Production of excessive levels of reactive oxygen species (ROS) in the vascular endothelium is a common pathogenic pathway in many dangerous conditions, including acute lung injury, ischemia-reperfusion, and inflammation. Ineffective delivery of antioxidants to the endothelium limits their utility for management of these conditions. In this study, we devised a novel translational antioxidant intervention targeted to the vascular endothelium using PEG-liposomes loaded with EUK-134 (EUK), a potent superoxide dismutase/catalase mimetic. EUK loaded into antibody-coated liposomes (size 197.8±4.5 nm diameter, PDI 0.179±0.066) exerted partial activity in the intact carrier, while full activity was recovered upon liposome disruption. For targeting we used antibodies (Abs) to platelet-endothelial cell adhesion molecule (PECAM-1). Both streptavidin-biotin and SATA/SMCC conjugation chemistries provided binding of 125-150 Ab molecules per liposome. Ab/EUK/liposomes, but not IgG/EUK/liposomes: i) bound to endothelial cells and inhibited cytokine-induced inflammatory activation in vitro; and, ii) accumulated in lungs after intravascular injection, providing >60% protection against pulmonary edema in endotoxin-challenged mice (vs <6% protection afforded by IgG/liposome/EUK counterpart). Since the design elements of this drug delivery system are already in clinical use (PEG-liposomes, antibodies, SATA/SMCC conjugation), it is an attractive candidate for translational interventions using antioxidant molecules such as EUK and other clinically acceptable drugs.

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Section: Introductionmentioning

confidence: 99%

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Howard

Greineder

Hood

et al. 2014

Journal of Controlled Release

Self Cite

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“…Uncaging in the microvascular endothelium, not loaded with the Ca 2ϩ -cage, did not increase ROS (data not shown), ruling out the possibility that the uncaging-induced microvascular ROS increase was a nonspecific effect of dye leakage across the alveolar membrane. PEG-catalase scavenges extracellular H 2 O 2 (31). Microvascular infusion of PEGcatalase completely inhibited the uncaging-induced microvascular ROS increase (Fig.…”

Section: L109 Alveolar Pore Formation Initiates Acid-induced Lung Injurymentioning

confidence: 83%

Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation

Westphalen

Monma

Islam

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Westphalen K, Monma E, Islam MN, Bhattacharya J. Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation. Am J Physiol Lung Cell Mol Physiol 303: L107-L116, 2012. First published May 4, 2012 doi:10.1152/ajplung.00206.2011Although gastric acid aspiration causes rapid lung inflammation and acute lung injury, the initiating mechanisms are not known. To determine alveolar epithelial responses to acid, we viewed live alveoli of the isolated lung by fluorescence microscopy, then we microinjected the alveoli with HCl at pH of 1.5. The microinjection caused an immediate but transient formation of molecule-scale pores in the apical alveolar membrane, resulting in loss of cytosolic dye. However, the membrane rapidly resealed. There was no cell damage and no further dye loss despite continuous HCl injection. Concomitantly, reactive oxygen species (ROS) increased in the adjacent perialveolar microvascular endothelium in a Ca 2ϩ -dependent manner. By contrast, ROS did not increase in wild-type mice in which we gave intraalveolar injections of polyethylene glycol (PEG)-catalase, in mice overexpressing alveolar catalase, or in mice lacking functional NADPH oxidase (Nox2). Together, our findings indicate the presence of an unusual proinflammatory mechanism in which alveolar contact with acid caused membrane pore formation. The effect, although transient, was nevertheless sufficient to induce Ca 2ϩ entry and Nox2-dependent H2O2 release from the alveolar epithelium. These responses identify alveolar H2O2 release as the signaling mechanism responsible for lung inflammation induced by acid and suggest that intra-alveolar PEG-catalase might be therapeutic in acid-induced lung injury.calcium; hydrogen peroxide; nitric oxide synthase 2; nitric oxide; reactive oxygen species; catalase; flash photolysis; resealing; clodronate THE GASTRIC AND THE PULMONARY epithelial surfaces are potentially exposed to highly concentrated HCl. The gastric epithelium secretes the acid at pH 1-2; the pulmonary epithelium encounters the acid following aspiration of gastric contents. Although a 200-m-thick mucus layer protects the gastric epithelium from acid injury (4), the much thinner layer of surfactant (6) is likely to provide relatively little protection to alveoli. Large aspirations cause severe lung inflammation, leading to acute lung injury (ALI) that associates with high mortality and morbidity (21). Mild aspirations prime the lung for secondary pneumonitis (30,34). No specific treatment is available for acid-induced ALI.An unsolved problem in the understanding of acid-induced ALI relates to the question of how the injury initiates following the first contact of acid with the alveolar membrane. Particularly lacking is the absence of studies defining the immediate alveolar response to the acid contact. Although animal studies confirm that airway instillation of highly concentrated acid (pH Ͻ2) causes ALI, these studies have largely focused on lung responses occurring well after the injury has alread...

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“…Even in intact ECs, endothelial function can be impaired due to generation of reactive oxygen species (ROS) following graft reperfusion (reviewed in 16,17,88 104,105 . In a porcine jugular-carotid interposition model, vein grafts had increased O 2 − production, decreased SOD activity, and greater lipid accumulation compared to arterial grafts at 1 month 106 .…”

Section: Endothelial Injury and Loss Of Endothelial Vasoprotective Famentioning

confidence: 99%

Gene Therapy for the Prevention of Vein Graft Disease

Mueller

Kontos

2015

Translating Gene Therapy to the Clinic

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Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate ischemic symptoms. Technological advancements have led to dramatic increases in the use of percutaneous and endovascular approaches, yet surgical revascularization (bypass surgery) with autologous vein grafts remains a mainstay of therapy for both coronary and peripheral artery disease. Although bypass surgery is highly efficacious in the short-term, long-term outcomes are limited by relatively high failure rates as a result of intimal hyperplasia, which is a common feature of vein graft disease.

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Targeted modulation of reactive oxygen species in the vascular endothelium

Cited by 49 publications

References 122 publications

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation

Gene Therapy for the Prevention of Vein Graft Disease

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