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Glutathione (GSH) in Lung, Respiratory, Pulmonary Disease
(Cystic Fibrosis, COPD, Emphysema)


Glutathione: in defense of the lung.
Kelly FJ.
[Food Chemistry Toxicology. 1999; volume 37, number 9-10, pages 963-966.] Oxidative stress is implicated in the pathology of numerous diseases of the lung. These include cystic fibrosis, chronic obstructive airway disease and asthma. The lung, like many other tissues, has a range of antioxidant defences which help to maintain a balanced redox status. These antioxidants are present in the intracellular, the vascular and extracellular respiratory tract lining fluid (RTLF) compartments. The reduced glutathione (GSH) content of RTLF is particularly high and new findings are beginning to reveal the role that the RTLF GSH pool plays in defending the lung.

Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis
Roum, James H., Zea Borok, Noel G. McElvaney, George J. Grimes, Allan D. Bokser, Roland Buhl and Ronald G. Crystal. [Journal of Applied Physiology 1999 Jul;87(1):438-43] Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered to 7 individuals with CF. ELF total, reduced and oxidized glutathione increased suggesting adequate RES delivery and utilization of GSH. PMA-stimulated superoxide anion (O2.) release by ELF inflammatory cells decreased after GSH therapy. This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O2. release. No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF, and support the rationale for further clinical evaluation.

Systemic deficiency of glutathione in cystic fibrosis
Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG. [J Appl Physiol 1993 Dec;75(6):2419-24] One process contributing to the airway derangement is the chronic burden of oxidants released by inflammatory cells on the respiratory epithelial surface. With this background, we hypothesized that glutathione in respiratory epithelial lining fluid (ELF) in CF patients might be oxidized and/or diminished in amount compared with that in normal subjects. As predicted, ELF in CF patients was characterized by a deficiency of glutathione, but this was secondary to a reduction in reduced glutathione. Unexpectedly, there was also a marked deficiency of reduced glutathione in plasma; i.e., the glutathione "deficiency" observed in ELF in CF patients is not limited to the site of the inflammation but is systemic. Although the etiology of this generalized deficiency of extracellular glutathione is unknown, it is important in considering options for treating the concomitant and devastating lung pathology in this disorder.

Lymphocyte glutathione levels in children with cystic fibrosis
Lands LC, Grey V, Smountas AA, Kramer VG, McKenna D. [Chest 1999 Jul;116(1):201-5] Lung disease in cystic fibrosis (CF) is characterized by a neutrophilic inflammatory response. This can lead to the production of oxidants, and to oxidative stress in the lungs. Glutathione (GSH) represents the primary intracellular antioxidant, and provides an important defense in the epithelial lining fluid.... lymphocyte GSH reflects lung GSH concentrations, .....the inverse correlation between lymphocyte GSH concentration and lung function as a reflection of upregulation of GSH production by lung epithelial tissue in response to oxidative stress ....correlation between lymphocyte GSH concentration and nutritional status as a reflection of the role of cysteine in hepatic glutamine metabolism....the increased demand for GSH production in the face of ongoing inflammation suggests a potential role for supplementation with cysteine donors.

Erythrocytic glutathione in cystic fibrosis. A possible marker of pulmonary dysfunction
Mangione S, Patel DD, Levin BR, Fiel SB. [Chest 1994 May;105(5):1470-3] We chose patients with CF because this disease is characterized by severe bronchial inflammation and marked oxidant-antioxidant imbalance. Although the GSH concentration of the two study groups was not significantly different, the RBC GSH concentration of patients with CF had a greater variability and was also inversely and significantly correlated to tests of pulmonary function. These data indicate a large and significant interindividual variability of erythrocytic antioxidants in patients with CF, with a compensatory, but probably inadequate, increase in patients with more severe respiratory deterioration. Red blood cell GSH concentration may thus provide a biologic marker for disease severity and a rationale for antioxidant manipulation in these patients.

Oxidative stress and regulation of glutathione in lung inflammation
Rahman I, MacNee W. [Eur Respir J. 2000 Sep;16(3):534-54.]

Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. 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. 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 gamma-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. This review describes the redox control and involvement of nuclear factor-kappaB and activator protein-1 in the regulation of cellular glutathione and gamma-glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant-mediated susceptibility/tolerance, gamma-glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

Treatment of obstructive airway disease with a cysteine donor protein supplement: a case report
Lothian B, Grey V, Kimoff RJ, Lands LC. Department of Pediatrics, McGill University Health Centre-Montreal Children's Hospital, Montreal, Quebec, Canada.[Chest 2000 Mar;117(3):914-6]
Case Study of a patient with Chronic Obstructive Pulmonary Disorder (COPD) - Oxidant/ antioxidant imbalance can occur in obstructive airways disease as a result of ongoing inflammation. Glutathione (GSH) plays a major role in pulmonary antioxidant protection. As an alternative or complement to anti-inflammatory therapy, augmenting antioxidant protection could diminish the effects of inflammation. We describe a case of a patient who had obstructive lung disease responsive to corticosteroids, and low whole blood GSH levels. After 1 month of supplementation with a whey-based oral supplement designed to provide GSH precursors, whole blood GSH levels and pulmonary function increased significantly and dramatically. The potential for such supplementation in pulmonary inflammatory conditions deserves further study.

Evidence of a defective thiol status of alveolar macrophages from COPD patients and smokers. Chronic obstructive pulmonary disease
Tager M, Piecyk A, Kohnlein T, Thiel U, Ansorge S, Welte T. [Free Radic Biol Med 2000 Dec;29(11):1160-5] In increasing numbers of pulmonary diseases an association with a loss of intracellular thiols, mainly glutathione, is postulated. Therefore, the quantitative measurement of thiols within different viable cells is a possible metabolic parameter for cellular function and defense capacity of all pulmonary immune cells including alveolar macrophages (AM), that are highly compromised by oxidative stress. AM obtained from bronchoalveolar lavage (BAL) of smokers and patients with chronic obstructive pulmonary disease (COPD) showed a significant thiol deficiency compared to a nonsmoker/non-COPD group. Lowest thiol concentrations (47% of control) were detected within the smoker(+)/COPD(+) group. This intracellular thiol deficiency significantly correlated with reduced lung function. With regard to the tightly regulated thiol metabolism of immune cells, these results imply the onset of functional disturbances in thiol deficient AM.

Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema
Engelen MP, Schols AM, and others. [Am J Respir Crit Care Med 2000 Jan;161(1):98-103.] "Chronic obstructive pulmonary disease (COPD) is often characterized by an impaired skeletal muscle energy metabolism, which is at least partly related to chronic hypoxia and a reduced diffusing capacity. This study illustrates that reduced glutamate levels in skeletal muscle of patients with emphysema are possibly related to an enhanced glycolytic activity and associated with decreased glutathione levels."

Frequent paracetamol use and asthma in adults
Shaheen SO, Sterne JA, Songhurst CE, Burney PG. [Thorax 2000 Apr;55(4):266-70] BACKGROUND: The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma....RESULTS: Paracetamol use was positively associated with asthma...amongst cases increasing paracetamol use was associated with more severe disease. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not. CONCLUSIONS: Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.

Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart- lung transplantation
Behr J, Maier K and others. [Transplantation 2000 May 15;69(9):1856-60.] "Reduced glutathione was positively correlated with forced expiratory volume... We conclude that excessive oxidative stress and a lack of glutathione are associated with BOS after H/LTX and may play relevant roles in the development of this disorder."

The effects of chronic alcohol abuse on pulmonary glutathione homeostatis
Moss M, Guidot DM, and others. [Am J Respir Crit Care Med 2000 Feb;161(2 Pt 1):414-9.] "This is the first report that chronic alcohol abuse alters glutathione homeostasis in the human lung, and suggests a potential mechanism by which chronic alcohol abuse predisposes susceptible patients to develop ARDS (acute respiratory distress syndrome). Recently, we determined that chronic ethanol ingestion in rats decreased the alveolar epithelial lining fluid (ELF) concentration of the antioxidant glutathione (GSH), which is a characteristic finding in patients with ARDS. However, the effects of chronic alcohol abuse on the human alveolar epithelium are essentially unknown.

Characterization of N-acetylcysteine and ambroxol in antioxidant therapy
Gillissen A and Nowak D. [Respir Med 1998 Apr;92(4):609-23.] "This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol." Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach.

Does N-acetyl-L-cysteine influence cytokine response during early human septic shock?
Spapen H, Zhang HB, and others. [Chest 1998 Jun;113(6):1616-24.] In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.


 


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