N-Acetylcysteine Administration during the First Week of Life Does Not Improve Lung Function in Extremely Low Birth Weight Infants

Sandberg, Kenneth; Fellman, Vineta; Stigson, Lennart; Thiringer, K; Hjalmarson, Ola

doi:10.1159/000080089

Cited by 55 publications

(29 citation statements)

References 24 publications

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“…for 6 d (95). The study showed no reduction in survival or the incidence or severity of BPD at 36 wk corrected age or improved pulmonary function when the infants were studied at term (96).…”

Section: Antioxidant Therapies: Enzymatic and Nonenzymatic Approachesmentioning

confidence: 78%

Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details

2009

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ABSTRACT:Reactive oxygen species (ROS) serve as cell signaling molecules for normal biologic processes. However, the generation of ROS can also provoke damage to multiple cellular organelles and processes, which can ultimately disrupt normal physiology. An imbalance between the production of ROS and the antioxidant defenses that protect cells has been implicated in the pathogenesis of a variety of diseases, such as cancer, asthma, pulmonary hypertension, and retinopathy. The nature of the injury will ultimately depend on specific molecular interactions, cellular locations, and timing of the insult. This review will outline the origins of endogenous and exogenously generated ROS. The molecular, cellular, pathologic, and physiologic targets will then be discussed with a particular emphasis on aspects relevant to child development. Finally, antioxidant defenses that scavenge ROS and mitigate associated toxicities will be presented, with a discussion of potential therapeutic approaches for the prevention and/or treatment of human diseases using enzymatic and nonenzymatic antioxidants. . This review will focus on-1) origins of ROS: environment, cells, and cellular components; 2) molecular targets: classic and novel macromolecular targets and associated toxicity in infants and children; 3) antioxidant defenses: developmental regulation and vulnerabilities; and 4) antioxidant therapies: enzymatic and nonenzymatic approaches. Origins of ROSOxygen has a unique molecular structure and is abundant within cells. It readily accepts free electrons generated by normal oxidative metabolism within the cell, producing ROS, such as O 2 ·Ϫ and hydroxyl radical (HO · ), as well as the oxidant H 2 O 2 . Processes causing uncoupling of electron transport can enhance the production of ROS, with mitochondria being a major source (4). However, other cellular components, such as endoplasmic reticulum-bound enzymes, cytoplasmic enzyme systems, and the surface of the plasma membrane, also contribute (5,6). Activity of multiple enzyme systems, such as the cytochrome P 450 monoxygenase system, xanthine oxidoreductase, nitric oxide synthases, and several others involved in the inflammatory process (cyclooxygenase and lipoxygenase), can also increase the generation of ROS.

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Section: Antioxidant Therapies: Enzymatic and Nonenzymatic Approachesmentioning

confidence: 78%

Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details

2009

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“…Our data do not allow use to speculate how a particular antioxidant may affect hyperoxic damage in the peripheral arterial chemoreceptors in human infants. Of interest, the use of NAC in preterm infants during the first week of life has not been shown to reduce the incidence of bronchopulmonary dysplasia (18,19), another morbidity of premature birth that is associated with hyperoxic exposure. Preterm infants may not effectively deacetylate NAC to cysteine, which is necessary for the molecule to function as a precursor for glutathione (20).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Hyperoxia on Reactive Oxygen Species (ROS) in Rat Petrosal Ganglion Neurons During Development Using Organotypic Slices

Kwak

Gauda

2006

Pediatr Res

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Hyperoxia, during development in rats, results in hypoxic chemosensitivity ablation, carotid body hypoplasia, and reduced chemoafferents. We hypothesized that hyperoxia increases reactive oxygen species (ROS) in cell bodies of chemoafferents. Organotypic slices of petrosal-nodose ganglia from rats at day of life (DOL) 5-6 and 17-18 were exposed to 8%, 21%, or 95% O 2 for 4 h in the presence or absence of the ROS-sensitive fluorescent indicator, CM-H 2 DCFDA, and propidium iodide was used to determine the relationship between cell death and oxygen tension. In tissue slices from DOL 5-6 rats, fluorescence intensity was 182.5 Ϯ 2.9 for hypoxia, 217.5 Ϯ 3.3 for normoxia, and 336.6 Ϯ 3.8 for hyperoxia, (mean Ϯ SEM, p Ͻ 0.001, ANOVA). Normoxia increased ROS levels by 19.2% from hypoxia (p Ͻ 0.01) with a further increase of 54.8% from normoxia to hyperoxia (p Ͻ 0.001). In tissue slices from DOL 17-18 rats, ROS levels increased with increasing oxygen tension but were less than in younger animals (p Ͻ 0.01, ANOVA). The antioxidants, NAC and TEMPO-9-AC, attenuated ROS levels and cell death. Electron microscopy demonstrated that hyperoxia damages the ultrastructure within petrosal ganglion neurons. Hyperoxic-induced increased levels of ROS in petrosal ganglion neurons may contribute to loss of hypoxic chemosensitivity during early postnatal development. N umerous studies in mammalian species support a role for peripheral arterial chemoreceptors in stabilizing ventilation at a critical period during early postnatal development, which establishes rhythmogenesis that is sustained throughout life (1,2). The components of the peripheral arterial chemoreceptors are found within the carotid body that is located in the bifurcation of the carotid artery and consists of three major neuronal components that include: 1) type I chemosensory cells, also known as glomus cells, which contain neurotransmitters and autoreceptors; 2) type II cells, which are similar to supportive glial cells; and 3) chemoafferent nerve fibers from the carotid sinus nerve, a branch of the IX cranial nerve, with cell bodies in the petrosal ganglion (PG) (3,4).Exposure to chronic hyperoxia, during the first weeks of postnatal development, depresses ventilatory responses to subsequent acute hypoxia in newborn animals and in premature infants (5-7). Hyperoxic exposure in newborn rat pups is cytotoxic to peripheral arterial chemoreceptors as evidenced by hypoplasia of the carotid body and a 41% reduction in the number of chemoafferent neurons (8). The mechanisms leading to cytotoxic changes in the carotid body and the reduction in chemoreflexes after hyperoxicexposure during early postnatal development are unknown. In other model systems, hyperoxia is associated with increased production of ROS, including superoxide, hydroxyl radical, and hydrogen peroxide, which can contribute to cellular damage via lipid peroxidation, enzyme inactivation, and protein and nucleic acid oxidation, resulting in apoptosis or necrosis (9). Using a novel ex vivo organotypic s...

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“…The synthesis of glutathionine (an endogenous scavenger of free radicals) is limited by the availability of cysteine. In a multicentre RCT, no significant differences were found in the incidence or severity of BPD [57] or in lung function [58]. N-acetyl cysteine, however, was started at age 36 h [57], which may have been too late.…”

Section: Antioxidantsmentioning

confidence: 96%

Medicines used in respiratory diseases only seen in children

Lenney¹,

Al²,

Bont³

et al. 2009

European Respiratory Journal

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Detailed literature searches were carried out in seven respiratory disease areas. Therapeutic evidence for efficacy of medicinal products was assessed using the Grades of Recommendation, Assessment and Evaluation (GRADE) methodology, as well as an assessment of safety and side-effects.Systemic corticosteroids may reduce the development of bronchopulmonary dysplasia but have serious side-effects. Antioxidants need further study to demonstrate whether they have long-term benefits. Treatments for acute bronchiolitis have shown little benefit but new antiviral and monoclonal antibodies need further assessment. Well-constructed studies are needed to confirm the value of inhaled corticosteroids and/or montelukast in the management of viralinduced wheeze. Corticosteroids are the treatment of choice in croup. Minimal or no information is available for the treatment of congenital lung abnormalities, bronchiolitis obliterans and interstitial lung disease.

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N-Acetylcysteine Administration during the First Week of Life Does Not Improve Lung Function in Extremely Low Birth Weight Infants

Cited by 55 publications

References 24 publications

Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details

Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details

The Effect of Hyperoxia on Reactive Oxygen Species (ROS) in Rat Petrosal Ganglion Neurons During Development Using Organotypic Slices

Medicines used in respiratory diseases only seen in children

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