Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells

Wu, Feng; Schuster, David P.; Tyml, Karel; Wilson, John X.

doi:10.1016/j.freeradbiomed.2006.10.033

Cited by 86 publications

(97 citation statements)

References 45 publications

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“…Ascorbate may also have a role in down-regulating hypoxia-inducible transcription factor (HIF)-1a protein levels (35). Ascorbate inhibits endothelial cell nicotinamide adenine dinucleotide phosphatereduced oxidase (36), and decreases the lipid peroxidation that leads to the initiation of local and systemic inflammation (37)(38)(39). Deferoxamine alone is used clinically in chronic iron overload (37) and as an antidote in acute iron poisoning (40), and it was found to decrease protein tyrosine nitration (41).…”

Section: Discussionmentioning

confidence: 99%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

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We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gasinduced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorineexposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the postexposure administration of ascorbate and deferoxamine.Keywords: epithelial injury; epithelial repair; mucosubstances; ascorbate; deferoxamine; aerosol Chlorine is essential to global industry and to global public health. According to the World Chlorine Council (http://www. worldchlorine.org), 14.4 million metric tons were produced in North America in 2008, and 62.8 million metric tons were produced globally. Water treatment makes up only 5% of the world's use of chlorine. The majority of chlorine is used in the production of plastics such as polyvinyl chloride (1). It is also used as a bleaching agent for pulp and paper production, as feedstock in the production of chlorinated solvents used in metalworking, in dry cleaning, in electronics, and in pharmaceutical production (1-6).Only 20 American states contain facilities that produce chlorine, but every American state has facilities that use chlorine. This results in the shipping of chlorine by railcar, and increases the potential for large-scale accidents. According to the Environmental Protection Agency, chlorine gas was related to 518 serious accidents over a 5-year period during the 1990s (1). Multiple-casualty exposures to chlorine have resulted from industrial accidents involving chlorine ta...

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Section: Discussionmentioning

confidence: 99%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

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“…8 and 9). Other groups have shown that the up-regulation of p47phox contributes to the inflammatory pathology observed in other disease states, including cancer, and cardiovascular and renal disease (47)(48)(49)(50). Thus, the therapeutic utility of suppressive ODN may be considerable if they can reduce p47phox expression in these other inflammatory conditions.…”

Section: Figurementioning

confidence: 99%

Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

Sato¹,

Shimosato²,

Alvord

et al. 2008

The Journal of Immunology

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Inhalation of silica-containing dust particles induces silicosis, an inflammatory disease of the lungs characterized by the infiltration of macrophages and neutrophils into the lungs and the production of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). Synthetic oligodeoxynucleotides (ODN) expressing “immunosuppressive motifs” were recently shown to block pathologic inflammatory reactions in murine models of autoimmune disease. Based on those findings, the potential of suppressive ODN to prevent acute murine silicosis was examined. In vitro studies indicate that suppressive ODN blunt silica-induced macrophage toxicity. This effect was associated with a reduction in ROS production and p47phox expression (a subunit of NADPH oxidase key to ROS generation). In vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation, as manifest by fewer infiltrating cells, less cytokine/chemokine production, and lower levels of ROS (p < 0.01 for all parameters). Treatment with suppressive ODN also reduced disease severity and improved the survival (p < 0.05) of mice exposed to silica.

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“…39, [123][124][125][126] Vitamin C, a potent water-soluble scavenger of free radicals, reduces monocyte adhesion to endothelial cells, inhibits LDL oxidation, decreases inactivation of NO and stimulates eNOS activity. 125,127) Vitamin C has been shown to improve the function of endothelium in patients with cardiovascular diseases. 128) Moreover, vitamin C has been noted to prevent homocysteine-induced impairment of vascular endothelial function.…”

Section: Antioxidants On Endothelial Dysfunctionmentioning

confidence: 99%

Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions

Balakumar¹,

Koladiya

Ramasamy

et al. 2008

JOURNAL OF HEALTH SCIENCE

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Endothelium forms an innermost lining of blood vessel and it regulates the vascular tone and permeability. A healthy vascular endothelium is antiatherogenic in nature because of its properties such as inhibition of platelet aggregation, adhesion cascades, smooth muscle cell proliferation and leukocyte adhesion. Vascular endothelial dysfunction (VED) is associated with reduced synthesis and release of nitric oxide, proinflammatory and prothrombotic properties followed by diminished vasodilation. VED has been implicated in the pathogenesis of artherosclerosis, hypertension, myocardial infarction, heart failure, renal failure and stroke. Various pharmacological interventions such as angiotensin converting enzyme (ACE) inhibitors, statins, insulin sensitizers, L-arginine as well as agents that target endothelial nitric oxide synthase (eNOS) "coupling" such as folates or tetrahydrobiopterin (BH4) have been noted to improve the function of vascular endothelium. In this review, we discussed various recently developed pharmacological interventions to improve the function of endothelium. Moreover, the novel targets sites involved in the pathogenesis of vascular endothelial dysfunction have been delineated.

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Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells

Cited by 86 publications

References 45 publications

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions

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