Oxidants, Antioxidants, and Respiratory Tract Lining Fluids

Cross, Carroll E.; Vliet, Albert van der; O’Neill, Charles; Louie, Samuel; Halliwell, Barry

doi:10.2307/3432237

Cited by 127 publications

(161 citation statements)

References 48 publications

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“…This is probably why the initial histological abnormality of CF fetuses occurs in submucosal glands (1,2), because in the absence of SCN Ϫ from the serous cells, unconsumed H 2 O 2 would be expected to irritate and harm the secreting glands, leading to inflammation and injuries. Duox activity indirectly stimulates mucin expression by epithelial cells (37); and mucin has a protective effect in that it scavenges ROS, including H 2 O 2 (38). The tissue-harming effects of H 2 O 2 may contribute to the inflammation observed in the digestive system and the lungs of CF patients in the absence of clinical infection.…”

Section: Discussionmentioning

confidence: 99%

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

Szép

Lü

2009

Proc. Natl. Acad. Sci. U.S.A.

125

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Cystic fibrosis (CF) is a pleiotropic disease, originating from mutations in the CF transmembrane conductance regulator (CFTR). Lung injuries inflicted by recurring infection and excessive inflammation cause Ϸ90% of the morbidity and mortality of CF patients. It remains unclear how CFTR mutations lead to lung illness. Although commonly known as a Cl ؊ channel, CFTR also conducts thiocyanate (SCN ؊ ) ions, important because, in several ways, they can limit potentially harmful accumulations of hydrogen peroxide (H 2O2) and hypochlorite (OCl ؊ ). First, lactoperoxidase (LPO) in the airways catalyzes oxidation of SCN ؊ to tissue-innocuous hypothiocyanite (OSCN ؊ ), while consuming H2O2. Second, SCN ؊ even at low concentrations competes effectively with Cl ؊ for myeloperoxidase (MPO) (which is released by white blood cells), thus limiting OCl ؊ production by the enzyme. Third, SCN ؊ can rapidly reduce OCl ؊ without catalysis. Here, we show that SCN ؊ and LPO protect a lung cell line from injuries caused by H 2O2; and that SCN ؊ protects from OCl ؊ made by MPO. Of relevance to inflammation in other diseases, we find that in three other tested cell types (arterial endothelial cells, a neuronal cell line, and a pancreatic ␤ cell line) SCN ؊ at concentrations of >100 M greatly attenuates the cytotoxicity of MPO. Humans naturally derive SCN ؊ from edible plants, and plasma SCN ؊ levels of the general population vary from 10 to 140 M. Our findings raise the possibility that insufficient levels of antioxidant SCN ؊ provide inadequate protection from OCl ؊ , thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis, neurodegeneration, and certain cancers.hydrogen peroxide ͉ hypochlorite ͉ hypothiocyanite ͉ lactoperoxidase ͉ myeloperoxidase

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Section: Discussionmentioning

confidence: 99%

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

Szép

Lü

2009

Proc. Natl. Acad. Sci. U.S.A.

125

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“…Cigarette smoke/air particulate-mediated lung injury Alveolar cells are normally covered in a thin protective layer of epithelial fluid, which is rich in antioxidants such as GSH [194]. It has been reported that incubation with extracellular GSH and increasing intracellular GSH levels protect against oxidant stress in alveolar type II cells [7,195].…”

Section: Antioxidant Protective Genesmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

808

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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“…Much more recently there has been much interest in the composition of the epithelial lining fluid (ELF) of the lung, that part of the structure which is in direct contact with the inhalant mix, above and beyond the physiology and pathophysiology of surfactants (Collard et al, 2004;Cross et al, 1994;Nishiki et al, 1976;Schock et al, 2001). Catalase is one ingredient of epithelial lining fluid but as the probable total volume of this thin layer in the adult lung is less than 10 ml spread across a surface area in excess of 880,000 cm² (Cross et al, 1994), and appears in the ELF only late in development ( Kaarteenaho-Wiik and Kinnula, 2004), this is not much of a defense for a premature newborn experiencing a sudden order of magnitude increase in pulmonary oxygen content, from 10-12 up to 110-120 Torr.…”

Section: Discussionmentioning

confidence: 99%

On the pulmonary toxicity of oxygen: III. The induction of oxygen dependency by oxygen use

Shanklin

2010

Experimental and Molecular Pathology

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Oxygen is central to the development of neonatal lung injury. The increase in oxygen exposure of the neonatal lung during the onset of extrauterine air breathing is an order of magnitude, from a range of 10-12 to 110-120 Torr. The contributions of oxygen and the volume and pressure relationships of ventilatory support to lung injury are not easily distinguished in the clinical setting. Sequential changes in inspired air or 100% oxygen were studied in 536 newborn rabbits without ventilatory support. Bilateral cervical vagotomies (BCV) were performed at 24 hours post natal to induce ventilatory distress which eventuates in hyaline membrane disease. The sequences applied yielded evidence for an induced state of oxygen dependency from oxygen use which was reflected in differences in survival and the extent of pulmonary injury. The median survival for animals kept in air throughout was 3 hours. Oxygen before vagotomy or during the first 3 hours afterwards extended the survival significantly but produced more extensive, more severe, and more rapid lung lesions. Returning animals to air after prior oxygen exposure reduced the number of survivors past 10 hours and shortened the maximum survival in those groups. These features indicate the development of a dependency of the defense mechanisms on the availability of oxygen at the higher level for metabolic and possibly other aspects of the pulmonary and systemic response to injury, beyond the usual physiological need.Subset analysis revealed additive and latent effects of oxygen and demonstrated a remarkable rapidity in onset of severe lesions under some circumstances, illustrating the toxicity of oxygen per se.

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Oxidants, Antioxidants, and Respiratory Tract Lining Fluids

Cited by 127 publications

References 48 publications

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

Oxidative stress and regulation of glutathione in lung inflammation

On the pulmonary toxicity of oxygen: III. The induction of oxygen dependency by oxygen use

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