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Oxidative Stress and Pulmonary Vascular Disorders

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Studies on Pediatric Disorders

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Abstract

When reactive oxygen species (ROS) production exceeds the antioxidant quenching capacity, the resulting condition is termed oxidative stress. Normally, oxidative stress triggers a compensatory increase in the major antioxidant enzymes: superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). However, multiple studies in humans and animals have shown that the overproduction of ROS coupled with the failure of the antioxidant ROS scavenging system contributes to the pathogenesis of numerous pediatric vascular disorders including pulmonary hypertension (PH), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and sickle cell disease (SCD). Vascular ROS are generated by nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in cellular membranes, by xanthine oxidase (XO) in the cytosol, and by mitochondria themselves. In addition, low tetrahydrobiopterin (BH4), the rate-limiting cofactor for endothelial nitric oxide synthase (eNOS) function, uncouples the enzyme and decreases nitric oxide (NO) and increases ROS production. Boosting antioxidants and suppressing ROS production are now important therapeutic goals in the management of vascular pathologies in children.

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Abbreviations

ADMA:

Asymmetrical dimethylarginine

BH4 :

Tetrahydrobiopterin

BPD:

Bronchopulmonary dysplasia

CHD:

Congenital heart disease

CPAP:

Continuous positive airway pressure

CrAT:

Carnitine acetyltransferase

DUOX:

Dual oxidase

eNOS:

Endothelial NOS

ET-1:

Endothelin-1

FAD:

Flavin adenine dinucleotide

GPx:

Glutathione peroxidase

GSH:

Glutathione

GS-SG:

Glutathione disulfide

iNOS:

Inducible NOS

IPAH:

Idiopathic pulmonary arterial hypertension

NAC:

N-acetylcysteine

NAD+:

Nicotinamide adenine dinucleotide

NADH:

Nicotinamide adenine dinucleotide, reduced form

NADPH:

Nicotinamide adenine dinucleotide phosphate

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOX:

Nicotinamide adenine dinucleotide phosphate oxidase

p47phox :

Protein 47 kD phagocyte oxidase

p67phox :

Protein 67 kD phagocyte oxidase

PAEC:

Pulmonary artery endothelial cells

PAH:

Pulmonary arterial hypertension

PAP:

Pulmonary artery pressure

PASMC:

Pulmonary artery smooth muscle cells

PBF:

Pulmonary blood flow

PEG:

Polyethylene glycol

PH:

Pulmonary hypertension

PPHN:

Persistent pulmonary hypertension of the newborn

PVR:

Pulmonary vascular resistance

RDS:

Respiratory distress syndrome

ROP:

Retinopathy of prematurity

ROS:

Reactive oxygen species

SCD:

Sickle cell disease

SO2 :

Sulfur dioxide

SOD:

Superoxide dismutase

UCP-2:

Uncoupling protein-2

VEGF:

Vascular endothelial growth factor

XO:

Xanthine oxidase

XOR:

Xanthine oxidoreductase

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Acknowledgments

The authors would like to acknowledge research support from the National Institutes of Health (HL60190, HL67841, HL084739, R21HD057406, HL61284, P01HL0101902) and the Foundation Leducq. Christine Gross is supported, in part, by a pre-doctoral fellowship from the Southeast Affiliates of the American Heart Association (12PRE12060224). Dr. Black also thanks the efforts of all past and present laboratory members.

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  1. The Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, 1459 Laney Walker Boulevard, CB 3211-B, Augusta, GA, 30912, USA

    Christine M. Gross, Saurabh Aggarwal, Ruslan Rafikov & Stephen M. Black Ph.D.

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  1. Christine M. Gross
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  2. Saurabh Aggarwal
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  3. Ruslan Rafikov
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  4. Stephen M. Black Ph.D.
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Correspondence to Stephen M. Black Ph.D. .

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  1. Dentistry and Pharmaceutical Sciences Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan

    Hirokazu Tsukahara

  2. Department of Pediatrics, Kansai Medical University, Osaka, Japan

    Kazunari Kaneko

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Gross, C.M., Aggarwal, S., Rafikov, R., Black, S.M. (2014). Oxidative Stress and Pulmonary Vascular Disorders. In: Tsukahara, H., Kaneko, K. (eds) Studies on Pediatric Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0679-6_27

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