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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