ArticlePDF Available

The Treatment of Pulmonary Diseases and Respiratory-Related Conditions with Inhaled (Nebulized or Aerosolized) Glutathione

Authors:

Abstract and Figures

Reduced glutathione or simply glutathione (gamma-glutamylcysteinylglycine; GSH) is found in the cytosol of most cells of the body. GSH in the epithelial lining fluid (ELF) of the lower respiratory tract is thought to be the first line of defense against oxidative stress. Inhalation (nebulized or aerosolized) is the only known method that increases GSH's levels in the ELF. A review of the literature was conducted to examine the clinical effectiveness of inhaled GSH as a treatment for various pulmonary diseases and respiratory-related conditions. This report also discusses clinical and theoretical indications for GSH inhalation, potential concerns with this treatment, its presumed mechanisms of action, optimal doses to be administered and other important details. Reasons for inhaled GSH's effectiveness include its role as a potent antioxidant, and possibly improved oxygenation and host defenses. Theoretical uses of this treatment include Farmer's lung, pre- and postexercise, multiple chemical sensitivity disorder and cigarette smoking. GSH inhalation should not be used as a treatment for primary lung cancer. Testing for sulfites in the urine is recommended prior to GSH inhalation. Minor side effects such as transient coughing and an unpleasant odor are common with this treatment. Major side effects such as bronchoconstriction have only occurred among asthma patients presumed to be sulfite-sensitive. The potential applications of inhaled GSH are numerous when one considers just how many pulmonary diseases and respiratory-related conditions are affected by deficient antioxidant status or an over production of oxidants, poor oxygenation and/or impaired host defenses. More studies are clearly warranted.
Content may be subject to copyright.
Advance Access Publication 17 May 2007 eCAM 2008;5(1)27–35
doi:10.1093/ecam/nem040
Review
The Treatment of Pulmonary Diseases and Respiratory-Related
Conditions with Inhaled (Nebulized or Aerosolized) Glutathione
Jonathan Prousky
1,2
1
The Canadian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto, ON M2K 1E2, Canada
and
2
International Primary Health Care, The External Program, University of London, London, UK
Reduced glutathione or simply glutathione (g-glutamylcysteinylglycine; GSH) is found in
the cytosol of most cells of the body. GSH in the epithelial lining fluid (ELF) of the
lower respiratory tract is thought to be the first line of defense against oxidative stress.
Inhalation (nebulized or aerosolized) is the only known method that increases GSH’s levels in
the ELF. A review of the literature was conducted to examine the clinical effectiveness of
inhaled GSH as a treatment for various pulmonary diseases and respiratory-related conditions.
This report also discusses clinical and theoretical indications for GSH inhalation, potential
concerns with this treatment, its presumed mechanisms of action, optimal doses to be
administered and other important details. Reasons for inhaled GSH’s effectiveness include its
role as a potent antioxidant, and possibly improved oxygenation and host defenses. Theoretical
uses of this treatment include Farmer’s lung, pre- and postexercise, multiple chemical sensitivity
disorder and cigarette smoking. GSH inhalation should not be used as a treatment for primary
lung cancer. Testing for sulfites in the urine is recommended prior to GSH inhalation. Minor
side effects such as transient coughing and an unpleasant odor are common with this treatment.
Major side effects such as bronchoconstriction have only occurred among asthma patients
presumed to be sulfite-sensitive. The potential applications of inhaled GSH are numerous
when one considers just how many pulmonary diseases and respiratory-related conditions are
affected by deficient antioxidant status or an over production of oxidants, poor oxygenation
and/or impaired host defenses. More studies are clearly warranted.
Keywords: aerosolized glutathione (GSH) – antioxidant – inhaled GSH – nebulized GSH –
reduced GSH
Introduction
Reduced glutathione or simply glutathione
(g-glutamylcysteinylglycine; GSH) is found in the cytosol
of most cells of the body (1). It is a tripeptide consisting
of glycine, cysteine and glutamate. GSH functions in
several enzyme systems within the body that assist with
the quenching of free radicals and the detoxification of
fat-soluble compounds (Table 1) (2–5). It also plays a
significant metabolic role in supporting many different
biochemical processes (e.g. amino acid transport, deox-
yribonucleic acid synthesis and immune system augmen-
tation) considered to be important mediators of health
status (6).
Glutathione in the epithelial lining fluid (ELF) of the
lower respiratory tract is thought to be the first line of
defense against oxidative stress (6). The ELF concentra-
tion of GSH is 140 times that of serum concentrations
with a redox ratio of 49 : 1 (7). In fact, alternations in
alveolar and lung GSH metabolism are widely recognized
as a central feature among many inflammatory lung
diseases (8–14). In healthy lungs, the oxidant burden is
balanced by local antioxidant defenses. However, in lung
For reprints and all correspondence: Jonathan Prousky, 1255 Sheppard
Avenue East, Toronto, Ontario, Canada MK2 1E2. Tel: 416-498-1255,
ext. 235; Fax: 416-498-1611; E-mail: jprousky@ccnm.edu
ß2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original workis
properly cited.
diseases cellular damage and injury is mediated by an
increased oxidant burden and/or decreased antioxidant
defenses.
In inflammatory lung diseases, supplementation with
exogenous sources of GSH would be necessary to reduce
the oxidant load and/or correct for antioxidant deficien-
cies within the lungs. A few published clinical studies
have shown the oral administration of GSH to be
ineffective at increasing plasma levels when given to
healthy subjects (15), or when used for the treatment of
hepatic cirrhosis (16). If the oral administration of GSH
cannot raise plasma levels in healthy and diseased
patients, it is doubtful that this method of delivery
would have any appreciable effects at increasing GSH
concentrations within the lungs.
Intravenous administration might be effective since it
bypasses the gastrointestinal tract, immediately enters the
blood stream, and presumably would saturate body
tissues such as the lungs. Unfortunately, the results of a
study did not show intravenous administration to be
effective at increasing GSH levels within the ELF (17).
When 600 mg of GSH was delivered intravenously to
sheep, the levels in the venous plasma, lung lymph and
ELF increased only for a very brief period of time.
However, when the same amount of GSH was delivered
through inhalation (nebulized or aerosolized), the base-
line GSH level in the ELF (45.7 10 mM) increased 7-fold
at 30-min (337 64 mM), remained above the baseline
level 1 h later (P50.001) and returned toward baseline
levels by 2 h. Despite this short-term increase in GSH
concentrations within the ELF, the inhalation method
did not significantly increase the amount of GSH in the
lung lymph, venous plasma and urine during the 2 h
study period. The authors of this report concluded that
inhalation specifically increased GSH levels at the lung
epithelial surface.
Given that inhalation is the only known method that
increases GSH levels in the ELF for a significant
duration, a review of the literature was conducted to
examine the clinical effectiveness of inhaled GSH
as a treatment for various pulmonary diseases and
respiratory-related conditions. Only reports involving
human subjects were included in the analysis. The clinical
and theoretical indications for GSH inhalation were
summarized and potential concerns with this treatment
reported. Other pertinent details such as its presumed
mechanisms of action and optimal doses to be adminis-
tered were compiled and evaluated.
Methods
Literature Search
Computer searches were conducted of English and non-
English language articles in the Biomedical Reference
Collection (1984 to August 2006), CINAHL (1982 to
August 2006), MEDLINE (1965 to August 2006) and
Nursing and Allied Health Collection (1985 to August
2006) databases. Articles were searched with the key
search terms ‘Nebulized Glutathione,’ and ‘Glutathione’
in combination with ‘Aerosol’ OR ‘Inhalation.’ These
keywords were also searched with words related to
pulmonary and/or respiratory disease. To supplement
the search, references of the articles found from the initial
search were reviewed. Hand searching of relevant
journals was also completed as part of the search.
Selection of Articles
To be included in the final review, articles had to report
on the use and administration of inhaled GSH for
pulmonary diseases and respiratory-related conditions in
human subjects. Only peer-reviewed articles were
reviewed.
Quality Assessment
An evidence grade was determined for each article. These
evidence grades were adapted from the hierarchy of
evidence developed by the Oxford Centre of Evidence
Based Medicine (Table 2) (18).
Table 1. Enzyme systems involving glutathione
Enzyme system Function
Glutathione synthetase Gamma-glutamyl cycle.
Riboflavin-containing glutathione reductase Catalyzes the conversion of oxidized glutathione
(glutathione disulfide; GSSG) to its reduced form.
GSH transferase isoenzymes Conjugation of GSH with fat-soluble substances for
liver detoxification and the detoxification of
environmental carcinogens, such as those found in tobacco smoke.
Selenium-containing glutathione
peroxidase (GPX)
Protects cells from hydrogen peroxides and lipid hydroperoxides.
If not neutralized, these peroxides will damage cellular membranes
and other vital cellular components.
Leukotriene C
4
synthase Conjugation of leukotriene A
4
with GSH, resulting in the generation
of leukotrienes C
4
. Gamma-glutamyl transpeptidase then metabolizes
leukotrienes C
4
to leukotrienes D
4
.
28 GSH in pulmonary diseases and respiratory-related conditions
Results
A total of 12 reports were screened (9,10,17,19–27). Only
one report was excluded because it involved the use of
inhaled GSH in sheep (17). In total, 11 articles were
found to meet the inclusion criteria and were included in
this review (9,10,19–27). Table 3 displays the character-
istics of the studies included in this review.
Discussion
Based exclusively on the published evidence included in
this review, inhaled GSH is potentially indicated for the
following clinical conditions: cystic fibrosis (CF), chronic
otitis media with effusion (OME), HIV seropositive
individuals, idiopathic pulmonary fibrosis (IPF) and
chronic rhinitis. These conditions were chosen since the
published studies were of good quality, received A and B
evidence grades, and their respective results demonstrated
benefits from the use of GSH inhalation.
Inhaled GSH cannot be recommended as a potential
treatment for emphysema since the quality of evidence is
lacking at the present time. The emphysema case report
had notable limitations since serial spirometry was not
documented, and the placebo effect could not be
ruled-out (22). However, this does not necessarily
indicate that GSH inhalation would be of no benefit
for emphysema patients. There is experimental and
human data demonstrating a link between GSH, oxidant-
derived damage and possible protection against the
development of emphysema. An in vitro study demon-
strated that GSH could retard the oxidant-mediated
down-regulation of a-1-proteinase inhibitor activity in
smokers’ emphysema (28). This finding is important since
one of the principal pathophysiological mechanisms of
emphysema is the down-regulation of this enzyme by
means of oxidative damage (29). Moreover, in a recent
review of lung GSH and cigarette smoke-induced airway
disease, increased GSH in the ELF of chronic smokers
was presumed to be a protective adaptive mechanism
against the development of chronic obstructive pulmon-
ary disease (COPD) (30). Considering that not all chronic
smokers go on to develop COPD, the authors in that
review pointed out that genetic variations in the
molecular mechanisms that regulate GSH metabolism
might explain why some individuals are better protected
against the development of COPD. It thus appears that
emphysema patients are subjected to progressive tissue
damage due, in part, to the consequences of GSH
deficiency and/or genetic variations in GSH metabolism.
Since GSH inhalation would presumably offer both
antioxidant protection and GSH replenishment, this
method of treatment would potentially benefit emphy-
sema patients.
Asthma is another condition where inhaled GSH
cannot be recommended since this treatment caused
notable side effects (e.g. breathlessness, bronchoconstric-
tion and cough) in the cited study (21). These side effects
were linked primarily to the production of sulfites that
occurred when GSH was in solution. GSH inhalation
should continue to be explored as a potential treatment
for asthma. None of the asthma patients in the study had
their urine tested for sulfites. A positive test for sulfites
would have eliminated these patients from entering the
study. Accordingly, the results might have been much
more favorable if patients without sulfite sensitivities
were included.
This issue of asthma and sulfite sensitivities is an
important one for clinicians to be mindful of. Sulfites are
found in beer, wine, restaurant salad bars, seafood,
potatoes, processed foods and many pharmaceuticals
(31). Many asthma patients report being sensitive to
sulfites. In an Australian study, 30% of asthmatic
patients reported being sensitive to sulfites in wine (32).
A more recent and rigorous scientific study, however,
demonstrated that asthma patients can tolerate varying
amounts of sulfites in wines ranging from 20, 75 or 150
parts per million (ppm) (33). Only a small minority of
patients in this study (4 of 24 self-reported wine-sensitive
asthmatics) exhibited reactions when challenged with
300 ppm of sulfites. One report indicated that 4–8% of
asthmatics are sensitive to sulfites (34). Other reports
have estimated the incidence of sulfite sensitivity to be
around 5–11% (35,36). Even though the exact percentage
of sulfite-sensitive asthmatics is difficult to ascertain,
sulfite sensitivity is an important factor to assess when
using or evaluating research done on inhaled GSH.
Future Research Directions
There are additional clinical conditions that might benefit
from this type of treatment, but further studies are
necessary. One such condition is Farmer’s lung (FL),
which is a hypersensitivity pneumonitis caused by the
inhalation of thermophilic actinomycetes and spores of
Aspergillus specie (11). A study was undertaken to
investigate the effect of pulmonary GSH levels after
hay exposure in patients with FL and in asymptomatic
farmers (AF) (11). Fifteen symptomatic patients with FL
Table 2. Grades of evidence
A Systematic reviews of randomized controlled trials
and/or randomized controlled trials with or without
double-blind placebo control.
B Systematic reviews of observational studies and/or
high-quality observational studies including
cohort and case-control studies and/or cohort
‘outcomes’ research and/or nonrandomized
controlled trials.
C Case-series, case-reports, and/or poor-quality
cohort and case-control studies.
D Expert opinion without explicit critical appraisal
or based on physiology, bench research or
‘first principles.’
eCAM 2008;5(1) 29
Table 3. Summary of articles demonstrating the effectiveness of inhaled glutathione for the treatment of pulmonary diseases and respiratory-related
conditions
Reference Condition NDosages of inhaled
GSH
Outcome Evidence grade
(21) Asthma Eight asthma patients
[mean age, 29 7
(standard deviation;
SD) years]
600 mg once weekly for
3 months
A subset of patients
with clinically stable
mild asthma
experienced a
bronchoconstrictor
effect when treated with
inhaled GSH.
A: Randomized
placebo-controlled trial
(23) Chronic otitis media
with effusion
(chronic OME)
30 patients (3–12 years of
age; mean age, 5.8 years)
and 30 controls (3–12 years
of age; mean age, 6.1 years)
600mg of GSH in 4 ml
of saline subdivided
into five 2-min sessions
by nasal aerosol every
3–4 waking h for
2 weeks
GSH should be
considered for the
nonsurgical
management of
chronic OME.
A: Randomized
placebo-controlled trial
(24) Cystic fibrosis (CF) Nine patients [mean age,
16.1 1.44 (SD) years]
received the
S-nitrosoglutathione
(GSNO) and
11 patients [mean age,
19.9 3.45 (SD) years]
received the phosphate-
buffered saline (PBS)
solution
0.05 ml/kg of 10 mM
GSNO
The treatment group
showed a modest
improvement in
oxygenation that was
thought to be
independent of the
physiological effects of
nitric oxide.
A: Randomized
placebo-controlled trial
(27) CF 19 patients (6–19 years of
age) were randomized to
treatment [mean age,
13.3 4.1 (SD) years] or
placebo groups [mean age,
12.9 4.9 (SD) years]
Total daily dose
administered to the
patients in the
treatment group was
66 mg/kg of body
weight
GSH can improve
clinical parameters in
CF patients, and that
effective treatment
should include the
correction of GSH
deficiency.
A: Randomized
placebo-controlled trial
(9) Idiopathic
pulmonary
fibrosis (IPF)
10 patients with IPF [mean
age, 46 3 (SD) years] and
19 normal nonsmokers
[mean age, 36 3
(SD) years]
600 mg twice daily for
3 days
Inhaled GSH might be
beneficial among IPF
patients by reversing the
oxidant–antioxidant
imbalance.
B: Nonrandomized con-
trolled trial
(19) Human
immunodeficiency
virus (HIV)
seropositive
individuals
14 HIV seropositive
individuals [mean
age, 32 2 (SD) years]
600 mg twice daily for
3 days
It is a reasonable
therapeutic strategy to
augment the deficient
GSH levels of the lower
respiratory tracts of
HIV seropositive
individuals.
B: Cohort ‘outcomes’
research
(20) Chronic rhinitis 13 patients with chronic
rhinitis and 13 healthy
subjects (4–15 years of age
for all subjects; mean age,
8.2 years)
600 mg daily for 14 days Statistically significant
improvement in nasal
obstruction, rhinorrhea
and ear fullness.
B: Nonrandomized
controlled trial
(10) CF Seven CF patients [mean
age, 25 1 (SD) years]
600 mg of GSH for
3 days
Inhalation therapy with
GSH does normalize
the respiratory
epithelial surface
oxidant–antioxidant
balance in CF patients.
B: Cohort ‘outcomes’
research
(25) CF 21 patients with CF (16–37
years of age for all
subjects)
300 or 450 mg three
times daily for 14 days
Inhaled GSH
can permeate the lower
airways of the lungs
and improve important
parameters of lung
function in CF patients
despite not having any
effect upon markers of
oxidative injury.
B: Cohort ‘outcomes’
research
(continued)
30 GSH in pulmonary diseases and respiratory-related conditions
[mean age, 42 1 (SD) year] were compared with 10 AF
[mean age, 43 1 (SD) year] serving as the control group.
All patients had baseline lung function testing and testing
at various time intervals following hay exposures. The
authors of this study concluded that FL and AF patients
have characteristically different intrapulmonary levels of
GSH, and that the pathogenesis of FL is likely related to
GSH regulatory mechanisms. They also speculated that
AF patients have a better ability to upregulate their
pulmonary GSH levels, which would protect them
against active disease. Clinical testing of inhaled GSH
in patients with FL is warranted.
The administration of GSH inhalation before and/or
immediately following exercise is another potential
application of this novel treatment. Exercise is a known
inducer of oxidative stress leading to free radical
production, which can encourage lipid peroxidation and
tissue damage among individuals with deficient and/or
impaired antioxidant systems. As stated in the beginning
of this report, selenium is a cofactor in the GPX enzyme
that protects cells from hydrogen peroxides and lipid
hydroperoxides. When under situations of oxidative
stress, the GPX enzyme will markedly increase in
the lungs as an antioxidant adaptive response (37).
By supplying more GSH to the lung tissues, more of
this enzyme might be available to help reduce the
production of free radicals associated with exercise.
Although these assumptions are very speculative, it does
seem possible and even logical that GSH inhalation
would benefit those who regularly exercise by increasing
exercise tolerance, and by maintaining and/or replenish-
ing the antioxidant systems within the lungs.
Multiple chemical sensitivity disorder (MCSD) is
another condition that might be clinically responsive to
this treatment. Patients with this disorder are known to
have bronchial hyperreactivity and even exhibit asthma-
like symptoms (38). Unlike asthma, MCSD is not
associated with atopy and immunoglobulin E (IgE)-
mediated allergic mechanisms (39). The prevailing theory
explaining the cause of MCSD is a fusion between two
separate theories—the neural sensitization and nitric
oxide/peroxynitrite theories (40). This fusion theory,
proposed by Pall, links long term potentiation of N-
methyl-d-aspartate (NMDA) receptors at the synapses of
nerve cells by glutamate and aspartate to an increased
production of nitric oxide and its oxidant product,
peroxynitrite (40,41). Treatment with antioxidants may
improve symptoms of MCSD by reducing the peroxy-
nitrite elevations and other biochemical dysfunctions that
are associated with such elevations (40,41). Glutathione
inhalation may be ideal since the primary route by which
patients with MCSD get triggered is through smelling
and breathing. Sulfite sensitivity would have to be
considered since inhaled GSH could provoke adverse
events. This treatment might be capable of providing
antioxidant protection to both the upper and lower
respiratory airways, which would theoretically help to
reduce the symptoms of MCSD and the production of
peroxynitrite. More research studies are necessary.
Two final conditions, cigarette smoking and lung
cancer, are worth mentioning since they are intimately
related to each other and are affected by GSH and its
related enzymes. These conditions are influenced by the
glutathione S-transferase (GST) group of enzymes that
are found in significant quantities in the bronchioles and
alveoli of the lungs (42), and in very high concentrations
in the bronchial epithelium (43). Among smokers, a lack
of the GST mu enzyme was thought to be associated with
a greater risk of lung cancer, especially if there was a
cancer and/or lung cancer history among the relatives of
the patients in this study (44). Since the GST mu enzyme
detoxify carcinogens in tobacco, any deficiency of this
enzyme was presumed to be associated with an increased
risk of lung cancer. However, a more recent study
pertaining to the GST group of enzymes found no such
association (45). In this meta-analysis, polymorphisms in
the GST genes had no associations or weakly positive
associations with risk factors for lung cancer. Despite the
Table 3. Continued
Reference Condition NDosages of inhaled
GSH
Outcome Evidence grade
(26) CF 17 patients with CF (18–29
years of age for all subjects;
mean age, 24 years)
450 mg three times daily
for 14 days
Inhaled GSH did not
affect the oxidative
status of the patients
who were tested, but it
did favorably modulate
their immune responses.
B: Cohort ‘outcomes’
research
(22) Emphysema One (95 year-old male) 120 mg of GSH in
office, then 120 mg
twice daily for 3 days,
and continuation
of treatment (dose
unknown) for 2 years
When the patient
returned for a follow-up
visit, he no longer
required the use of his
wheelchair and oxygen.
The striking results
were unexpected and
unlikely to be due to
placebo alone.
C: Case report
eCAM 2008;5(1) 31
need for more research, GSH inhalation might be
beneficial for smokers to augment their GST enzymes,
which would help facilitate the detoxification of carcino-
gens. Even though the best intervention for these patients
would be smoking cessation, many patients lack the
necessary willpower to quit. For these patients, regular
GSH inhalation might reduce oxidants generated from
cigarette smoke (10
14
free radicals/puff) (46), and the
epithelial lung injury associated with smoking (47).
For lung cancer patients, the use of GSH inhalation is
not recommended. Cancer cells use multiple mechanisms
(e.g. altered transport of a drug, inhibition of drug-
induced apoptosis and elevation of cellular GSH) to
circumvent the cytotoxic effects of chemotherapeutic
agents (48). Early research studies showed that GSH
was able to reduce cytotoxicity to chemotherapeutic
compounds by boosting the metabolism of drugs to less
active compounds, or by the detoxification of free
radicals (49,50). More recently, research has revealed
that the levels of a specific GST enzyme increases among
cancer cells with higher differentiation grades, and that
these drug-resistant gene products are found in lung
carcinomas at the time of surgical resection (51). There is
also speculation that GSH might be capable of repairing
drug-induced injury at the DNA level (48). A recent
review article has described the involvement of glu-
tathione in the detoxification or inactivation of platinum
drugs—the most commonly employed drugs for the
treatment of advanced stage lung cancer patients (52).
Based on this information, it would be unwise and
illogical to use GSH inhalation while lung cancer patients
are undergoing active chemotherapy treatment.
Mechanism of Action
Inhalation of GSH results in a mechanism of action
confined to the upper airways and lungs (Fig. 1), and will
not influence plasma levels to a significant degree. In the
studies that measured both lung and plasma levels of
GSH, the plasma levels remained essentially unchanged
following GSH inhalation. Seven of the studies included
in this review demonstrated that GSH inhalation
exerts its effects upon the lower respiratory tract
(9,10,19,24–27). The upper respiratory tract also appears
to benefit from GSH augmentation. Two studies invol-
ving patients with upper respiratory tract diseases showed
clinical benefits from GSH inhalation treatment (20,23).
The predominant mechanism responsible for GSH’s
therapeutic effects are probably related to its antioxidant
properties that offer protection against oxidative injury,
and/or assist with the normalization of the oxidant–
antioxidant balance within the upper and lower respira-
tory tract. Even though the majority of these studies
suggested that antioxidant protection was the principal
reason for the favorable treatment responses, some of the
studies were unable to demonstrate a change in markers
of oxidation from this treatment. More data is necessary
to confirm the precise nature of GSH’s antioxidant
properties within the upper and lower respiratory tract.
Additional explanations for GSH’s therapeutic effects
might include an improvement in host defenses (e.g.
increased cytotoxic lymphocytes), and better oxygenation
(e.g. an increase in oxygen saturation). GSH inhalation
produced clinically meaningful results in the majority of
diseases that were studied. Specifically, GSH inhalation
was shown to improve clinical markers of respiratory
function that inevitably impact upon quality of life and
disease progression. These improvements were the most
important outcomes and features of this novel treatment.
Considerations Prior to Initiating GSH Inhalation
The urine should be tested for sulfite sensitivity. A special
test strip can be dipped in the urine, and is known as the
‘EM-Quant 10013 Sulfite Test.’ It can be easily located
through any search engine on the Internet (53). Even
though instructions for sulfite testing have been published
elsewhere (54), a brief description of the procedure is
outlined below:
A random (fresh) urine sample is suitable, but a
first morning void may be preferable due to its
higher concentration. Once the test strip is
dipped in the urine (for 1 s), the reaction zone
changes color to indicate the concentration of
sulfites present. After 30 s, the color on the test
strip is compared to a color scale on the bottle
indicating the concentrations of sulfites in the
urine (can detect 10, 40, 80, 180 and 400 ppm of
sulfites). The resultant concentration should be
multiplied by a factor of 1.5 to provide the
amount of free sulfites in mg/l (ppm). The strip
will not detect below 10 ppm. The urine samples
should be preservative free, and the urinary pH
should also be tested with pH paper. If the urine
pH is below 6, then the amount of sulfites might
be underestimated by the test. In such cases,
consider adding sodium acetate or sodium
hydroxide to raise the pH to at least 7–10
(should not exceed a pH of 12), and then repeat
with a new test strip.
If the urine test were positive for sulfites (normally they
are absent), the use of inhaled GSH would be strictly
contraindicated.
Method of Delivery, Recommended Daily Dosages
and Side Effects
With a nebulizer, a solution of GSH is made into an
aerosol and is delivered to the upper respiratory tract
and the lungs through a mask that covers the nose
and mouth, or is delivered directly into the lungs via
a mouthpiece. Any compounding pharmacist would be
32 GSH in pulmonary diseases and respiratory-related conditions
able to prepare the solution of GSH at the desired
concentrations. The typical dosages used in the
studies cited in Table 3 were 600 mg once daily, 600 mg
twice daily, 900 mg daily, 1350 mg daily or a daily dose of
66 mg/kg of body weight. Better results are more likely to
be achieved with doses of at least 600 mg or more each
day. One of the studies used much larger doses (66 mg/kg
of body weight) since the authors speculated that these
would be necessary to replace half of the amount of GSH
that is produced each day (e.g. a 150 lb male synthesizes
10 g daily and would need 5 g as a replacement dose) (27).
When patients are unresponsive to doses in the range of
600–1350 mg per day, it might be suitable to try doses
that would replace half the estimated amount of GSH
that is synthesized each day. These gram doses might
yield better clinical results.
In terms of side effects, GSH inhalation is very safe.
Minor side effects such as mild coughing and an
unpleasant odor were reported in some of the studies
included in this review. These minor side effects, better
described as mild nuisance problems, were not severe
enough to cause any of the study participants to
discontinue treatment with inhaled GSH. The only
worrisome or potentially life-threatening side effect to
note is bronchoconstriction, which would be more likely
to occur among sulfite-sensitive asthma and MCSD
patients. However, if proper precautions such as sulfite
testing are done prior to treatment, this serious side effect
should be avoidable.
Monitoring the Clinical Response to Inhaled GSH
For pulmonary diseases or respiratory-related conditions,
baseline pulmonary function testing with a spirometer or
a simple peak flow meter is recommended prior to the
Mouth
Nasel Passages
Bronchioles
Ri
g
ht Lun
g
Left Lung
Inhaled GSH
Increases GSH concentrations
Increases antioxidant production
Decreases oxidant-induced damage
Increases host immune responses
(i.e. increases cytotoxic lymphocytes)
Increases oxygen saturation
Reduces ear fullness, nasal
obstruction and rhinorrhea
Improves pulmonary function
(i.e. increases FEV1 and FVC)
Figure 1. Inhaled GSH’s mechanism of action. GSH, reduced glutathione; FEV
1
, forced expiratory volume in 1 s; FVC, forced vital capacity.
eCAM 2008;5(1) 33
first treatment. After a prescribed period of treatment
time, pulmonary function tests should be repeated. This
will help to establish if there are any clinical improve-
ments from regular GSH inhalation.
Conclusions
GSH inhalation is an effective treatment for a variety of
pulmonary diseases and respiratory-related conditions.
Even very serious and difficult-to-treat diseases (e.g., CF,
IPF) yielded benefits from this novel treatment. GSH
inhalation is very safe, and rarely causes major or life-
threatening side effects. The potential applications are
numerous when one considers just how many pulmonary
diseases and respiratory-related conditions are affected by
deficient antioxidant status, poor oxygenation and/or
impaired host defenses. More studies are clearly
warranted.
Acknowledgments
The author would like to thank Mr Glen Carr and Mr
Andrew Dick for their wonderful illustration of GSH’s
mechanism of action.
References
1. Groff JL, Gropper SS, Hunt SM. Advanced Nutrition and Human
Metabolism, 2nd edn. St. Paul, MN: West Publishing Company,
1995, 165–6.
2. Bhagavan NV. Medical Biochemistry. Boston, MA: Jones and
Bartlett, 1992, 323–4.
3. Kidd PM. Glutathione: systemic protectant against oxidative and
free radical damage. Altern Med Rev 1997;2:155–76.
4. Tate SS, Meister A. Gamma-glutamyl transpeptidase: catalytic,
structural and functional aspects. Mol Cell Biochem 1981;39:357–68.
5. Yoshimoto T, Soberman RJ, Spur B, Austen KV. Properties of
highly purified leukotriene C
4
synthase of guniea pig lung. J Clin
Invest 1988;81:866–71.
6. Lomaestro B, Malone M. Glutathione in health and disease:
pharmacotherapeutic issues. Ann Pharmacother 1995;29:1263–73.
7. Cantin AM, North SL, Hubbard RC, Crystal RG. Normal alveolar
epithelial lining fluid contains high levels of glutathione. J Appl
Physiol 1987;63:152–7.
8. Rahman I, MacNee W. Oxidative stress and regulation of
glutathione in lung inflammation. Eur Respir J 2000;16:534–54.
9. Borok Z, Buhl R, Grimes GJ, Bokser AD, Hubbard RC,
Holroyd KJ, et al. Effect of glutathione on oxidant-antioxidant
imbalance in idiopathic pulmonary fibrosis. Lancet 1991;338:215–6.
10. Roum JH, Borok Z, McElvaney NG, Grimes GJ, Bokser AD,
Buhl R, et al. Glutathione aerosol suppresses lung epithelial surface
inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol
1999;87:438–43.
11. Behr J, Degenkolb B, Beinert T, Krombach F, Vogelmeier C.
Pulmonary glutathione levels in acute episodes of Farmer’s lung.
Am J Respir Crit Care Med 2000;161:1968–71.
12. Buhl R, Vogelmeier C. Therapy for lung diseases with anti-oxidants.
Pneumologie 1994;48:50–6.
13. Buhl R, Meyer A, Vogelmeier C. Oxidant-protease interaction in
the lung. Prospects for antioxidant therapy. Chest 1996;110
(6 Suppl):267S–72S.
14. Gressier B, Lebegue S, Gosset P, Brunet C, Luyckx M, Dine T,
et al. Protective role of glutathione on alpha 1 proteinase inhibitor
inactivation by myeloperoxidase system. Hypothetic study for
therapeutic strategy in the management of smoker’s emphysema.
Fundam Clin Pharmacol 1994;8:518–24.
15. Witschi A, Reddy S, Stofer B, Lauterburg BH. The
systemic availability of oral glutathione. Eur J Clin Pharmacol
1992;43:667–9.
16. Cook GC, Sherlock S. Results of a controlled clinical trial of
glutathione in cases of hepatic cirrhosis. Gut 1965;6:472–6.
17. Buhl R, Vogelmeier C, Critenden M, Hubbard RC, Hoyt RF Jr,
Wilson EM, et al. Augmentation of glutathione in the fluid lining
the epithelium of the lower respiratory tract by directly administer-
ing glutathione aerosol. Proc Natl Acad Sci USA 1990;87:4063–7.
18. Centre for Evidence-Based Medicine: 5http://www.cebm.net/
levels_of_evidence.asp#levels42006.
19. Holroyd KJ, Buhl R, Borok Z, Roum JH, Bokser AD, Grimes GJ,
et al. Correction of glutathione deficiency in lower respiratory tract
of HIV seropositive individuals by glutathione aerosol treatment.
Thorax 1993;48:985–9.
20. Testa B, Mesolella M, Testa D, Giuliano A, Costa G, Maione F,
et al. Glutathione in the upper respiratory tract. Ann Otol Rhinol
Laryngol 1995;104:117–9.
21. Marrades RM, Roca J, Barbera
`JA, de Jover L, MacNee W,
Rodriguez-Roisin R. Nebulized glutathione induces bronchocon-
striction in patients with mild asthma. Am J Respir Crit Care Med
1997;156:425–30.
22. Lamson DW, Brignall MS. The use of nebulized glutathione in the
treatment of emphysema: a case report. Altern Med Rev
2000;5:429–31.
23. Testa B, Testa D, Mesolella M, D’Errico G, Tricarico D, Motta G.
Management of chronic otitis media with effusion: the role of
glutathione. Laryngoscope 2001;111:1486–9.
24. Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS,
Gaston B. Acute effects of aerosolized S-nitrosoglutathione in cystic
fibrosis. Am J Respir Crit Care Med 2002;165:922–6.
25. Griese M, Ramakers J, Krasselt A, Starosta V, van
Koningsbruggen S, Fisher R, et al. Improvement of alveolar
glutathione and lung function but not oxidative state in cystic
fibrosis. Am J Respir Crit Care Med 2004;169:822–8.
26. Hartl D, Starosta V, Maier K, Beck-Speier I, Rebhan C, Becker BF,
et al. Inhaled glutathione decreases PGE2 and increases
lymphocytes in cystic fibrosis lungs. Free Radic Biol Med
2005;39:463–72.
27. Bishop C, Hudson VM, Hilton SC, Wilde C. A pilot study of the
effect of inhaled buffered glutathione on the clinical status of
patients with cystic fibrosis. Chest 2005;127:308–17.
28. Gressier B, Lebegue S, Gosset P, Brunet C, Luyckx M, Dine T,
et al. Protective role of glutathione on alpha-1-proteinase inhibitor
inactivation by the myeloperoxidase system. Hypothetic study for
therapeutic strategy in the management of smokers’ emphysema.
Fundam Clin Pharmacol 1994;8:518–24.
29. Wiedemann HP, Stoller JK. Lung disease due to alpha 1-antitrypsin
deficiency. Curr Opin Pulm Med 1996;2:155–60.
30. Rahman I, MacNee W. Lung glutathione and oxidative stress:
implications in cigarette smoke-induced airway disease. Am J
Physiol 1999;277(Lung Cell Mol Physiol. 21);L1067–88.
31. Yang WH, Purchase ECR. Adverse reactions to sulfites. Can Med
Assoc J 1985;133:865–7880.
32. Vally H, de Klerk N, Thompson PJ. Alcoholic drinks: important
triggers for asthma. J Allergy Clin Immunol 2000;105:462–7.
33. Vally H, Thompson PJ. Role of sulfite additives in wine induced
asthma: single dose and cumulative dose studies. Thorax
2001;56:763–9.
34. Giffon E, Vervloet D, Charpin J. Suspicion on sulfites. Rev Mal
Respir 1989;6:303–10.
35. Nolan AL. The sulfite controversy. Food Eng 1983;00:84–589–9.
36. Twarog FJ. Metabisulfite sensitivity in asthma. Allergy Proc
1983;4:100–3.
37. Witshi H. Environmental agents altering lung biochemistry.
Fed Proc 1977;36:1631–4.
38. Kipen HM, Fiedler N. Environmental factors in medically
unexplained symptoms and related syndromes: the evidence
and the challenge. Environ Health Perspect 2002;110 (Suppl
4):597–9.
39. Elberling J, Linneberg A, Dirksen A, Johansen JD, Frolund L,
Madsen F, et al. Mucosal symptoms elicited by fragrance products
in a population-based sample in relation to atopy and bronchial
hyper-reactivity. Clin Exp Allergy 2005;35:75–81.
34 GSH in pulmonary diseases and respiratory-related conditions
40. Pall ML. Multiple chemical sensitivity the end of controversy.
5http://molecular.biosciences.wsu.edu/faculty/pall/pall_mcs.htm4
2006.
41. Pall ML. Elevated nitric oxide/peroxynitrite theory of multiple
chemical sensitivity: central role of N-methyl-D-aspartate receptors
in the sensitivity mechanism. Environ Health Perspect
2003;111:1461–4.
42. Awasthi YC, Singh SV, Ahmad H, Moller PC.
Immunohistochemical evidence for the expression of GST1, GST2,
and GST3 gene loci for glutathione S-transferase in human lung.
Lung 1987;165:323–32.
43. Anttila S, Hirvonen A, Vainio H, Husgafvel-Pursiainen K,
Hayes JD, Ketterer B. Immunohistochemical localization of
glutathione S-transferase in human lung. Cancer Res
1993;53:5643–8.
44. Cerrahoglu K, Kunter E, Isitmangil T, Oztosun AI, Isitmangil G,
Okutan O, et al. Can’t lung cancer patients detoxify
procarcinogens? Allerg Immunol 2002;34:51–5.
45. Ye Z, Song H, Higgins JPT, Pharoah P, Danesh J. Five glutathione
S-transferase gene variants in 23,452 cases of lung cancer and 30,397
controls: meta-analysis of 130 studies. PloS Med 2006;3:e91.
46. Nakayama T, Churh DF, Pryor W. Quantitative analysis of
the hydrogen peroxide formed in aqueous cigarette tar extracts.
Free Radic Biol Med 1989;7:9–15.
47. Lannan S, Donaldson K, Brown D, MacNee W. Effect of cogarette
smoke and its condensates on alveolar epithelial cell injury in vitro.
Am J Physiol 1994;266:L92–L100.
48. Iqbal MP. Mechanisms of drug resistance in cancer cells. Pak J
Med Sci 2003;19:118–27.
49. Arrick BA, Nathan CF. Glutathione metabolism as a determinant
of therapeutic efficacy: a review. Cancer Res 1984;44:4224–32.
50. Meister A. Selective modification of glutathione metabolism.
Science 1983;220:472–7.
51. Mattern J, Kooma
¨gi R, Volm M. Expression of drug resistance
gene products during progression of lung carcinomas. Oncol Rep
2002;9:1181–4.
52. Yang P, Ebbert JO, Sun Z, Weinshilboum RM. Role of the
glutathione metabolic pathway in lung cancer treatment and
prognosis: a review. J Clin Oncol 2006;24:1761–9.
53. EM-Quant 10013 Sulfite Test. 5http://www.galladechem.com/
catalog/test_strips/sulfite-test-strips-10-400-ppm-em-quant–1-pk-of-
100.htm42007.
54. Wright J, Littleton K. Defects in sulphur metabolism. Int Clin Nut
Rev 1989;9:118–9.
Received December 22, 2006; accepted February 13, 2007
eCAM 2008;5(1) 35
... Interestingly, GSH inhalation produces clinically significant results for most of the diseases studied. More specifically, GSH inhalation has shown improvement in respiratory function markers that impact quality of life and disease progression [61] . ...
... Based on the aforementioned information regarding pulmonary conditions, it would appear that inhalation ( Fig. 2 ) is one of the methods that can significantly increase the levels of GSH in the pulmonary epithelial lining fluid [61] . Previous studies on GSH inhalation have also revealed positive results for an array of additional conditions such as cystic fibrosis, chronic otitis, HIV positive patients, idiopathic pulmonary fibrosis and chronic rhinitis [61] . ...
... Based on the aforementioned information regarding pulmonary conditions, it would appear that inhalation ( Fig. 2 ) is one of the methods that can significantly increase the levels of GSH in the pulmonary epithelial lining fluid [61] . Previous studies on GSH inhalation have also revealed positive results for an array of additional conditions such as cystic fibrosis, chronic otitis, HIV positive patients, idiopathic pulmonary fibrosis and chronic rhinitis [61] . Medical experts should, however, beware of the dispersion of particles in patients undergoing nebulization, which is why this route of administration is strongly recommended for patients who do not respond well to other interventional strategies and administration routes. ...
Article
Full-text available
Ever since its emergence, the highly transmissible and debilitating coronavirus disease spread at an incredibly fast rate, causing global devastation in a matter of months. SARS-CoV-2, the novel coronavirus responsible for COVID-19, infects hosts after binding to ACE2 receptors present on cells from many structures pertaining to the respiratory, cardiac, hematological, neurological, renal and gastrointestinal systems. COVID-19, however, appears to trigger a severe cytokine storm syndrome in pulmonary structures, resulting in oxidative stress, exacerbated inflammation and alveolar injury. Due to the recent nature of this disease no treatments have shown complete efficacy and safety. More recently, however, researchers have begun to direct some attention towards GSH and NAC. These natural antioxidants play an essential role in several biological processes in the body, especially the maintenance of the redox equilibrium. In fact, many diseases appear to be strongly related to severe oxidative stress and deficiency of endogenous GSH. The high ratios of ROS over GSH, in particular, appear to reflect severity of symptoms and prolonged hospitalization of COVID-19 patients. This imbalance interferes with the body's ability to detoxify the cellular microenvironment, fold proteins, replenish antioxidant levels, maintain healthy immune responses and even modulate apoptotic events. Oral administration of GSH and NAC is convenient and safe, but they are susceptible to degradation in the digestive tract. Considering this drawback, nebulization of GSH and NAC as an adjuvant therapy may therefore be a viable alternative for the management of the early stages of COVID-19.
... Few clinical studies have demonstrated that oral administration of GSH was ineffective in increasing plasma levels of healthy controls (52), while its intravenous administration increases its levels in the pulmonary epithelial lining fluid, albeit for a short period of time (53). Based on these preliminary studies, it appears that inhalation is one of the methods that can significantly increase the levels of GSH in the pulmonary epithelial lining fluid (54). Studies on GSH inhalation have revealed positive results for cystic fibrosis, chronic otitis, HIV positive patients, idiopathic pulmonary fibrosis and chronic rhinitis (54). ...
... Based on these preliminary studies, it appears that inhalation is one of the methods that can significantly increase the levels of GSH in the pulmonary epithelial lining fluid (54). Studies on GSH inhalation have revealed positive results for cystic fibrosis, chronic otitis, HIV positive patients, idiopathic pulmonary fibrosis and chronic rhinitis (54). However, practitioners should be vigilant about the dispersion of particles in patients undergoing nebulization, which is why this route of administration should only be considered if the patient does not respond to adjunctive therapy intravenously. ...
... The recommended dose is 600-5000 mg per day, depending on response, and whether inhaled GSH is considered safe. Efficacy should be tested using a baseline pulmonary function test and a follow-up test after a prescribed time later [119] (. Fig. 51.4, ...
... Fig. 51.4 Inhaled GSH's mechanism of action. GSH, reduced glutathione; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity[119]. (Reprinted from Prousky[35]. ...
Chapter
Lung disease rivals the position for the top cause of death worldwide. Causes and pathology of the myriad lung diseases are varied, yet nutrition can either affect the outcome or support treatment in the majority of cases. This chapter explores the modifiable risk factors, from lifestyle changes to dietary intake to specific nutrients, anti-nutrients, and toxins helpful for the nutritionist or dietitian working with lung disease patients. General lung health is discussed, and three major disease states are explored in detail, including alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Although all lung diseases have diverse causes, many integrative and functional medical nutrition therapies are available and are not being utilized in practice today. This chapter begins the path toward better nutrition education for the integrative and functional medicine professional.
... The use of GSH precursors like N-acetyl cysteine, enhancers of nuclear factor erythroid 2-related factor 2 (Nrf2) like sulforaphane, melatonin, and many more molecules involved in antioxidant defense were proposed as supplementation of other idiopathic pulmonary fibrosis therapies (130). Inhaled (nebulized or aerosolized) reduced GSH to augment the deficient GSH levels of the lower respiratory tract has been used effectively in numerous pulmonary diseases and respiratory conditions like HIV seropositive individuals, cystic fibrosis and idiopathic pulmonary fibrosis, among others (131)(132)(133). GSH has clearly a regulatory role in inflammation and immunity (134). ...
Article
Full-text available
Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1–10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.
... Exposure to molds and mycotoxins perpetuates the oxidative stress situation which is the ground of neurodegenerative disorders. In case of oxidative stress, the level of GSH is significantly decreased; therefore, GSH and its precursors are reasonable choice to treat mycotoxin-induced neurotoxicity [155]. GSH in reduced state assist the numerous enzymes systems to detoxify the fat-soluble toxic compounds and act as antioxidant agent [156]. ...
Chapter
Numerous fungal species are fabricated into several paradigms of mycotoxins as secondary metabolites notably Fusarium, Aspergillus, and Penicillium. These toxic metabolites have significant impact on the brain health of human beings if entered through the food chain or from the direct exposure through the modulation of myriad molecular mechanistic signaling pathways. T-2 toxin, macrocyclic trichothecenes, fumonisin B1, and ochratoxin A are recognized as neurotoxic metabolites among the other mycotoxins. T-2 toxins and macrocyclic trichothecenes induce neuronal apoptosis and neuroinflammation. Fumonisin B1 inhibits ceramide synthesis and neurodegeneration in cerebral cortex. Ochratoxin A persuades the dopaminergic neuronal loss and apoptosis in striatum, substantia nigra, and hippocampus. This chapter reviews the biotransformation and detoxification of these mycotoxins in relation to their degrading enzymes. The therapeutic roles of glutathione, sequestering agents, probiotics, and sweat induction to mitigate mycotoxin-induced neurotoxicity have also been overviewed.
... In the epithelial lining fluid (ELF) of the lower respiratory tract, GSH is the first defence factor against oxidative stress. Inhalation of GSH is an effective treatment for various pulmonary diseases [45]. In lung inflammation, the neutrophils release hypochlorous acid (HOCl), which reacts with GSH secreted by the epithelial cells. ...
Article
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection.Drug SuggestionPirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. Conclusion The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.
... Since GSH has a short half-life, resulting in limited cellular uptake, several alternatives to increase intracellular levels of GSH have been developed (12)(13)(14)(15). Glutathione ethyl ester (GSH-EE) is one of these GSH alternatives, and has been shown to boost thiol content in cells through hydrolysis to release GSH (16,17). ...
Article
Full-text available
Background: Oxidative stress plays an important role in the pathogenesis of asthma. Glutathione (GSH) is considered to be one of the most important antioxidants. Our study systematically investigated the effect of the GSH alternative, glutathione ethyl ester (GSH-EE), on airway hyper-responsiveness (AHR) in mice. Methods: Sixty-three male specific pathogen-free mice were used. Asthma was induced using a single dose of ovalbumin (OVA). The normal group (n=15) received vehicle only [Al(OH)3 in saline]. Then, 48 mice were divided into two groups, including a control group who received sodium phosphate buffer (pH =7.4), and the GSH-EE group who received 0.1% GSH-EE. AHR was measured 2, 6, and 12 hours after exposure to nebulized OVA (0.01%). The animals were then sacrificed, and lung tissue and the bronchi-alveolar lavage fluid (BALF) were harvested. Factors involved in the antioxidant response to asthma were then measured in these tissues, including thiol content (from GSH and protein), γ-glutamylcysteine synthetase (γ-GCS) activity and expression, and nuclear factor-erythroid-2-related factor (Nrf2) expression. Results: The GSH-EE group showed a significant attenuation of AHR (P<0.01) 2 hours after OVA challenge, and significantly enhanced thiol contents by approximately 45% (P<0.05) at 2 and 6 hours after the last OVA challenge, compared to the control group. γ-GCS activity was also higher in the GSH-EE group compared to the control group at different time points (P<0.01). γ-GCSh and Nrf2 protein expression increased in the GSH-EE group and the control group compared with the normal group, but there was no statistically significant difference (P>0.05) between the GSH-EE group and the control group. Conclusions: GSH-EE supplementation can prevent AHR in asthmatic mice during the early stages. It may function by serving as a precursor for GSH biosynthesis and by protecting sulfhydryl groups from oxidation.
... 15 An optimal balance between physical and biological properties of the material carrying cells is required for clinical translation and additional issues regarding isolation and manipulation of cells need to be addressed. 16,17 A collagen-hydroxyapatite scaffold was able to commit human MSCs toward osteogenic differentiation in vitro. 18 In the present study, ADSCs were complexed with three-dimensional (3D) protein scaffolds for transplantation into the vaginas of irradiated rats. ...
Article
Full-text available
Objectives Cervical cancer, the most common female cancer after breast cancer, is typically treated using radiotherapy. However, pelvic radiotherapy can cause irreversible damage to the vagina, seriously affecting patients’ quality of life. In this study, protein scaffolds loaded with rat adipose-derived mesenchymal stem cells (ADSCs) were implanted into irradiated tissue to assess their healing potential. Methods We established a rat model of radiation-induced vaginal injury. Complexes (consisting of protein scaffolds loaded with ADSCs) were implanted into injury sites. Histological analysis were used to assess regeneration of the vaginal epithelium. RNA sequencing was used to study the therapeutic mechanism of the complexes. Results The complexes promoted vaginal epithelial cell regeneration, vaginal tissue repair and improved vaginal stenosis and contracture. Compared with rats transplanted with ADSCs, rats transplanted with complexes achieved better therapeutic effects. Conclusions Protein scaffold-ADSC complexes had a beneficial therapeutic effect on radiation-induced vaginal injury in rats and may serve as the basis of a novel therapeutic approach for radiation dermatitis.
Chapter
The impact of aging on the integrity of the outermost layer of our tissue, the epithelium, predisposes the older adult to dysfunction in these tissues found in the skin, lungs, eyes, and hair. As the foundation of health, the health status of the gut lining directs the status of other epithelial tissues due to the impact of nutritional deficiencies from malabsorption as well as the impact of the microbiome that exists on all of these external-facing surfaces. Both environments, the skin and the gut, host microbiomes of immense and diverse proportions. On its own, the gut performs innumerable functions, including but not limited to vitamin production, immune regulation, protection from pathogens, serum lipid modulation, and metabolism of xenobiotics and food components (Ellis et al. Microorganisms 7:550, 2019). The skin serves to maintain the cutaneous immune system. (Ellis et al. Microorganisms 7:550, 2019). Although the mechanisms are not fully elucidated, there are a few prevailing theories. Changes in gut flora due to stress, injury, or inflammation increase epithelial permeability in the gut, which triggers T-cell activation, disrupts tolerance, and leads to systemic inflammation that disturbs cutaneous homeostasis (Arck et al. Exp Dermatol 19:401–5, 2010). Another theory suggests increased gut permeability allows for direct migration of inflammatory products into systemic circulation (Cani et al. Diabetes 56:1761–72, 2007). The connection warrants further research but is likely due to a combination of both neurologic and immunologic responses to environmental changes (Ellis et al. Microorganisms 7:550, 2019). In this chapter, we highlight the most common concerns related to the skin, lungs, eyes, and hair for the older adult: xerosis, psoriasis, eczema, chronic obstructive pulmonary disease, macular degeneration, and alopecia.
Article
Reactive oxygen and nitrogen species can be generated endogenously (by mitochondria, peroxisomes, and phagocytic cells) and exogenously (by pollutions, UV exposure, xenobiotic compounds, and cigarette smoke). The negative effects of free radicals are neutralized by antioxidant molecules synthesized in our body, like glutathione, uric acid, or ubiquinone, and those obtained from the diet, such as vitamins C, E, and A, and flavonoids. Different microelements like selenium and zinc have no antioxidant action themselves but are required for the activity of many antioxidant enzymes. Furthermore, circulating blood proteins are suggested to account for more than 50% of the combined antioxidant effects of urate, ascorbate, and vitamin E. Antioxidants together constitute a mutually supportive defense against reactive oxygen and nitrogen species to maintain the oxidant/antioxidant balance. This article outlines the oxidative and anti-oxidative molecules involved in the pathogenesis of chronic obstructive lung disease. The role of albumin and alpha-1 antitrypsin in antioxidant defense is also discussed.
Article
Full-text available
The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (-SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (-SH ⇋ -S-S-). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/SH thiols, ascorbate, other small molecules) to the most complex (cellular-SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the ©P450 Phase II" enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of -SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is MAC (N-acetylcysteine).
Article
Full-text available
There are nine well accepted paradigms of human disease. The tenth may explain the features of multiple chemical sensitivity (MCS) and a group of related illnesses including chronic fatigue syndrome (CFS), fibromyalgia (FM) and posttraumatic stress disorder (PTSD); Gulf War syndrome appears to be a combination of all four. The elevated nitric oxide/peroxynitrite vicious cycle paradigm explains most of the most puzzling features of this group of previously unexplained illnesses (1-16) that afflict tens of millions of people in the U.S. and elsewhere. These illnesses have multiple overlaps with each other (2-5,13,16). They share many common symptoms and signs. They are repeatedly reported to be comorbid conditions. Cases of each of them typically show a common pattern of case initiation, with cases being preceded by and presumably induced by a short term stressor, only to be followed by a chronic illness that usually persists for life. These similarities have led many different researchers to propose that two, three or all four of them may share a common etiologic mechanism (3,5,16), but they were unable to suggest what that mechanism might be. The short term stressors reported to initiate these illnesses are very diverse. Six have very well documented roles as initiators, viral infection, bacterial infection, physical trauma (particularly head and neck trauma), organophosphate/carbamate pesticide* exposure, volatile organic solvent exposure and severe psychological stress. There are six additional stressors that are less well documented as initiators of these illnesses and thus may be viewed as candidate initiators. These latter six include pyrethroid pesticide exposure, organochlorine (chlordane or lindane) pesticide exposure, a protozoan infection (toxoplasmosis), ciguatoxin poisoning#, carbon monoxide poisoning and thimerosal exposure. All 12 of these are known to be able to initiate a sequence of events leading to increases in nitric oxide levels. Thus they all have a common biochemical end point, suggesting that they may act to initiate these illnesses through a common mechanism (1-5,7,13,16). The three classes of infection all act to raise nitric oxide levels primarily by inducing the inducible nitric oxide synthase (iNOS) whereas most of the others are known to act by increasing NMDA@ receptor activity and such NMDA activity is * The pesticides involved fall into discrete classes, based both on their chemical structure and biochemical mode of action in both insects and in humans. Organophosphate and carbamate pesticides both act as inhibitors of the enzyme acetylcholinesterase, the enzyme that gets rid of acetylcholine. The pyrethroid pesticides act to open sodium channels in the brain. The organochlorine pesticides act to inhibit what are known as GABAa receptors, sites at which the compound GABA acts in the brain. The interesting thing here is that although these all act at different targets in the brain, they all can produce a common response, involving excessive activity of the NMDA receptors in the brain and excessive nitric oxide. # Ciguatoxin is a toxic compound produced by certain tropical organisms which when eaten by tropical fish, make the fish toxic to people who eat them. The toxin called ciguatoxin or ciguatera toxin acts somewhat like the pyrethroid pesticides, leaving open sodium channels in the brain. @ The NMDA receptors are receptors for glutamate found primarily in the central and peripheral nervous system. They are called NMDA receptors because they are specifically stimulated by the compound N-methyl-D-aspartate whereas other
Article
Full-text available
When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 μmol·l−1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol·kg−1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic γ-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.
Article
Full-text available
Glutathione (GSH), a cysteine-containing tripeptide, functions as an antioxidant, provides cells with cysteine, and is required for optimal function of the immune system. Because the epithelial-lining fluid (ELF) of the lower respiratory tract normally contains high GSH levels and lung ELF GSH deficiency states can exist, we evaluated the feasibility of augmenting lung ELF GSH levels by (i) administering GSH to sheep i.v. and by direct aerosolization and then (ii) measuring the GSH levels in lung ELF, lung lymph, venous plasma, and urine. When GSH (600 mg) was administered i.v. (n = 11), GSH levels in venous plasma, lung lymph, and ELF rose, but only transiently, suggesting the i.v. route would not deliver adequate GSH to the alveolar epithelial surface. For directly administering GSH to the lung by the aerosol route, in vitro studies were first conducted to show that greater than 50% of a GSH solution could be converted to droplets less than 3 microns in aerodynamic diameter without oxidizing the GSH. To target functional GSH to the lower respiratory tract, an aerosolized solution of GSH (600 mg) was administered to sheep (n = 12). Significantly, the GSH level in ELF increased 7-fold at 30 min (preaerosol, 45.7 +/- 10 microM; 30-min postaerosol, 337 +/- 64 microM; P less than 0.001). The ELF GSH levels remained above baseline at 1 hr (P less than 0.01), returning toward baseline over a 2-hr period. In contrast, GSH levels in lung lymph, venous plasma, and urine were not significantly increased during the period--i.e., aerosol therapy selectively augmented the GSH levels only at the lung epithelial surface. Thus, functional GSH can be delivered by aerosol to directly augment the ELF GSH levels of the lower respiratory tract. Such an approach may prove useful in treating a variety of lung disorders.
Article
Development of drug resistance is a common problem in cancer chemotherapy. For the past several years, investigators have been striving hard to unravel mechanisms of drug resistance in cancer cells. Using different experimental models of cancer, some of the major mechanisms of drug resistance identified in mammalian cells include: (a) Altered transport of the drug [decreased influx of the drug; increased efflux of the drug (role of P-glycoprotein; role of polyglutamation; role of multiple drug resistance associated protein)], (b) Increase in total amount of target enzyme/protein (gene amplification), (c) Alteration in the target enzyme/protein (low affinity enzyme), (d) Elevation of cellular glutathione, (e) Inhibition of drug-induced apoptosis (mutation in p53 tumor suppressor gene; increased expression of bcL-xL gene). Other novel mechanisms in various types of cancer cells include: Over-expression of cytochrome P450 protein, ATP-binding cassette transporter BCRP, sodium channel protein, S-adenosylmethionine synthetase, and loss of functional retinoblastoma protein. An understanding of these mechanisms provides us the basis for the development of drugs which can specifically interact with the cause of resistance and restore the sensitivity of the tumor cell. This reversal of drug resistance has a significant role in modern day cancer chemotherapy.
Article
Sulfiting agents including sodium and potassium bisulfite and metabisulfite, sulfur dioxide, and sodium sulfate are recently identified food and drug adverse responsible for adverse reactions such as flushing, tingling, pruritis, urticaria, glottic edema, dysphagia, chest tightness, acute bronchospasm, cyanosis, and loss of consciousness. Foods which contain metabisulfite are listed in Table I. Metabisulfites are also present in some drugs such as aerosolized bronchodilators. The pathogenic mechanism is unknown. Approximately 3-5% of the asthmatic population reacts adversely to these sulfites. The FDA has recently recognized this potential hazard and a ban on the use of sulfiting agents in restaurants is being considered.
Article
Immunocytochemical studies demonstrate that significant amounts of glutathione S-transferase (GST) are associated with alveoli and bronchioles of human lung. The immunofluorescence in human lung sections was observed with the antibodies which were raised against GSTω and GSTα-ɛ of human liver and GSTπ of human placenta indicating that the isoenzymes corresponding to three gene loci, GST1, GST2, and GST3 are present in human lung. Presence of GST isoenzymes in significant amounts in bronchioles and alveoli of human lung indicate that these isoenzymes may play an important role in the detoxification of xenobiotics as well as in combating oxidative stress through glutathione peroxidase II activity.
Article
Environmental agents may enter the lung via the tracheobronchial tree or via the bloodstream. They can interact with lung cell metabolism and set in motion a sequence of events that leads to damage, adaptation, and repair. Biochemical signs of lung damage described include lipid peroxidation, decreased biosynthesis of macromolecules, depressed enzyme activities, and the binding of metabolites of the offending agent to tissue macromolecules. As a response to acute damage, lung can activate several biochemical pathways. The selenium-glutathione peroxidase system affords protection against lipid peroxidation and increased activity of superoxide dismutase provides oxygen tolerance. Biochemical adaptation occasionally occurs very quickly: the herbicides paraquat and diquat produce an acute loss of cellular NADPH in lung. This is accompanied by a sudden increase in pentose phosphate pathway activity. Biochemical events accompanying tissue repair following lung injury are increased synthesis of nucleic acids and of protein and enhanced enzymatic activity. The repair following lung damage caused by drugs may be inhibited by oxygen.
Article
Idiopathic pulmonary fibrosis (IPF) is characterised by alveolar inflammation, exaggerated release of oxidants, and subnormal concentrations of the antioxidant glutathione in respiratory epithelial lining fluid (ELF). Glutathione (600 mg twice daily for 3 days) was given by aerosol to 10 patients with IPF. Total ELF glutathione rose transiently, ELF oxidised glutathione concentrations increased, and there was a decrease in spontaneous superoxide anion release by alveolar macrophages. Thus, glutathione by aerosol could be a means of reversing the oxidant-antioxidant imbalance in IPF.