New Insights Into the Pathogenesis of Cystic Fibrosis

Abstract

The cystic fibrosis transmembrane regulator (CFTR) should no longer be viewed primarily as a ‘chloride channel’ but recognized as a channel that also controls the efflux of other physiologically important anions, such as glutathione (GSH) and bicarbonate. More effective approaches to cystic fibrosis treatment may result from this reconceptualization of the CFTR by researchers and clinicians. For example, oxidant damage in cystic fibrosis has been assumed to be a significant part of the pathophysiology of the disease. Generally speaking, antioxidant status in cystic fibrosis is compromised. However, until recently this was seen as secondary to the excessive chemoattraction of neutrophils in this disease caused by mutation of the CFTR protein, leading to a high oxidant burden. New findings suggest that the cystic fibrosis mutations in fact cause a primary dysfunction in the system of one of the body’s most important antioxidant and immune-signaling substances: the reduced GSH system. Cystic fibrosis mutations significantly decrease GSH efflux from cells without redundant channels to the CFTR; this leads to deficiency of GSH in the epithelial lining fluid of the lung, as well as in other compartments, including immune system cells and the gastrointestinal tract. This deficiency is exaggerated over time as the higher-than-normal oxidant burden of cystic fibrosis leads to successively larger decrements in GSH without the normal opportunity to fully recover physiologic levels. This GSH system dysfunction may be the trigger for initial depletion of other antioxidants and may also play a role in initiating the over-inflammation characteristic of cystic fibrosis. Proper GSH system functioning also affects immune system competence and mucus viscosity, both of relevance to cystic fibrosis pathophysiology. In a way, cystic fibrosis may be thought of as the first identified disease with GSH system dysfunction.
This overview provides a review of the most pertinent recent research findings in this area. Exogenous augmentation of GSH in the lung epithelial lining fluid is possible, and therapeutic approaches include administration of aerosolized buffered GSH, intravenous GSH, and oral GSH. However, it is important to remember that the pathophysiology of cystic fibrosis is multifactorial, and rectification of GSH system dysfunction in patients with cystic fibrosis will not eliminate all harmful effects of the disease. The promising results of two clinical trials of aerosolized buffered GSH in cystic fibrosis patients have been published or accepted for publication at the time of this writing. GSH depletion in lung epithelial lining fluid has also been noted in other respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory distress syndrome, and therapies to augment GSH may also be contemplated in these diseases.

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Treat Respir Med 2004; 3 (6): 353-363
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New Insights Into the Pathogenesis of
Cystic Fibrosis
Pivotal Role of Glutathione System Dysfunction and Implications for Therapy
Valerie M. Hudson
Brigham Young University, Provo, Utah, USA
The cystic fibrosis transmembrane regulator (CFTR) should no longer be viewed primarily as a ‘chloride
Abstract
channel’ but recognized as a channel that also controls the efflux of other physiologically important anions, such
as glutathione (GSH) and bicarbonate. More effective approaches to cystic fibrosis treatment may result from
this reconceptualization of the CFTR by researchers and clinicians. For example, oxidant damage in cystic
fibrosis has been assumed to be a significant part of the pathophysiology of the disease. Generally speaking,
antioxidant status in cystic fibrosis is compromised. However, until recently this was seen as secondary to the
excessive chemoattraction of neutrophils in this disease caused by mutation of the CFTR protein, leading to a
high oxidant burden. New findings suggest that the cystic fibrosis mutations in fact cause a primary dysfunction
in the system of one of the body’s most important antioxidant and immune-signaling substances: the reduced
GSH system. Cystic fibrosis mutations significantly decrease GSH efflux from cells without redundant channels
to the CFTR; this leads to deficiency of GSH in the epithelial lining fluid of the lung, as well as in other
compartments, including immune system cells and the gastrointestinal tract. This deficiency is exaggerated over
time as the higher-than-normal oxidant burden of cystic fibrosis leads to successively larger decrements in GSH
without the normal opportunity to fully recover physiologic levels. This GSH system dysfunction may be the
trigger for initial depletion of other antioxidants and may also play a role in initiating the over-inflammation
characteristic of cystic fibrosis. Proper GSH system functioning also affects immune system competence and
mucus viscosity, both of relevance to cystic fibrosis pathophysiology. In a way, cystic fibrosis may be thought of
as the first identified disease with GSH system dysfunction.
This overview provides a review of the most pertinent recent research findings in this area. Exogenous
augmentation of GSH in the lung epithelial lining fluid is possible, and therapeutic approaches include
administration of aerosolized buffered GSH, intravenous GSH, and oral GSH. However, it is important to
remember that the pathophysiology of cystic fibrosis is multifactorial, and rectification of GSH system
dysfunction in patients with cystic fibrosis will not eliminate all harmful effects of the disease. The promising
results of two clinical trials of aerosolized buffered GSH in cystic fibrosis patients have been published or
accepted for publication at the time of this writing. GSH depletion in lung epithelial lining fluid has also been
noted in other respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory distress
syndrome, and therapies to augment GSH may also be contemplated in these diseases.
Cystic fibrosis disease is the result of a mutation of the cystic colonization of the lungs by bacteria and fungi and auto-destruc-
fibrosis transmembrane regulator (CFTR) protein, resulting in tion of lung tissue by excessive inflammation even in the absence
missing or defective cellular anion efflux channels in epithelial of pathogen challenge (and accelerated by pathogen challenge
cells. Most cystic fibrosis patients ultimately die of respiratory when it occurs). The excessive inflammation has been linked to
failure, as a result of deterioration in pulmonary function. There the cystic fibrosis mutation itself and is associated with greater
are several causes for deterioration in lung function, including than normal chemoattraction for neutrophils as a result of higher

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354 Hudson
constitutive levels of, for example, interleukin (IL)-8.[1-8] The important roles of GSH, then, is to act as a water-soluble antioxi-
oxidant burden caused by such excessive inflammation appears to dant. Not only can it neutralize oxidants through an enzymatic
overwhelm natural antioxidant defenses. The resulting damage to pathway utilizing GSH peroxidase, it is also capable of neutraliz-
lung tissue allows for greater adhesion of pathogens,[9] in addition ing oxidants directly without the use of an enzymatic pathway.[16]
to reducing lung function directly.[10] In cystic fibrosis, however, epithelial cells still produce GSH
New research findings, however, suggest that the traditional normally, but one result is significant impairment of the ability of
view of disease pathogenesis needs some modification. It now cells that do not possess a channel redundant to the CFTR to efflux
appears that cystic fibrosis mutations cause a primary dysfunction GSH to fulfill its functions in the extracellular milieu.
in one of the most important antioxidant and immune-signaling Each antioxidant system – fat-soluble, water-soluble, and enzy-
substances: the reduced glutathione (GSH) system. Dysfunction in matic – protects the cell within its own sphere of action. Some
the GSH system may be the catalyst for initial depletion of other systems operate within the cytosol, which others operate at the cell
antioxidants and may play a role in priming and perpetuating membrane or are active in the extracellular milieu. GSH operates
excessive inflammation characteristic of cystic fibrosis. Neverthe- both within the cytosol and in the extracellular milieu. In these
less, it is important to remember that cystic fibrosis pathophysiolo- compartments, it is capable of directly reducing oxidants and it
gy is multifactorial and that not all cystic fibrosis disease manifes- also reacts with GSH peroxidase, located in the cell membrane, to
tations can be linked to GSH system dysfunction. neutralize oxidants. GSH is replenished in two ways: by interac-
This modification of the traditional view is in line with tion of GSH disulfide (GSSG) with the enzyme GSH reductase
cutting-edge cystic fibrosis research, which suggests that the sole and by synthesis of GSH within the cell (i.e. de novo or after
focus on the CFTR channel as a chloride efflux channel has cleavage of extracellular GSH and transport of component amino
obscured other significant functions associated with it. Current acids back into the cell). Circulation of GSH effluxed from cells
research now views the CFTR channel as, at the very least, a throughout the body may allow for higher levels of GSH particu-
chloride, bicarbonate, and GSH efflux channel. Undoubtedly this larly in the extracellular compartments, such as the lung.
list will be expanded in the future. This new and fundamental shift The various antioxidant systems are interdependent, to one
in the way the CFTR channel is viewed may allow for the degree or another, for proper function. The crippling of one system
development of innovative and effective therapies for cystic fibro- leads to decreased protection by other antioxidant systems. With-
sis. In this article, we will focus on the CFTR as a GSH efflux out GSH, as we have seen, GSH peroxidase is unable to function
channel and discuss its significance for the respiratory system. It is as an antioxidant.[17] Antioxidant systems such as GSH, ascorbic
worth noting that preliminary studies of the role of bicarbonate acid, tocopherol, and ubiquinol-10[18,19] are interdependent, and
secretion in the lung have shown that the lack of functional CFTR normal levels of each in reduced form are required to maintain
may result in a decrease in the pH of the cystic fibrosis lung, which
normal levels of the others in reduced form.[20] In addition, GSH
may also have pathologic consequences;[11,12] however, this find-
deficiency is linked to decreased activity of catalase and superox-
ing is disputed elsewhere.[13-15] The newly understood role of
ide dismutase.[20] GSH deficiency also taxes the fat-soluble antiox-
CFTR as a GSH and bicarbonate efflux channel also has important
idant systems by permitting greater levels of lipid peroxidation,
implications for gastrointestinal complications associated with
yielding damaging metabolites.[20-27] This genetic chink in the
cystic fibrosis. In this article, discussion will be confined to the
antioxidant armor of cystic fibrosis patients predisposes them to
effects of CFTR mutation on the respiratory system only.
have successively larger decrements in antioxidant protection over
time, as other antioxidants are consumed in greater quantities or
1. Understanding the Role of the Glutathione (GSH) left unused as a result of impaired GSH efflux.
System in Normal Lung Health
Furthermore, recent studies have demonstrated the importance
of S-glutathiolation of proteins under conditions of oxidative or
Virtually all cells of the body produce thiol-reduced GSH from
nitrosative stress.[28,29] To prevent irreversible loss of intracellular
the three amino acids glutamine, glycine, and cysteine. Cysteine
and extracellular protein function under such stress, mixed disul-
serves as the rate-limiting amino acid for GSH production. It is
fides are formed between protein cysteines and GSH. These S-
estimated that an adult male produces approximately 10g of GSH
glutathiolated proteins are more stable and can be dethiolated by
per day. Not only is GSH present in the cells of the body, it also
either non-enzymatic reduction or enzymatic cleavage of the disul-
bathes the extracellular spaces of the body, with high extracellular
fide bond. Thus, S-glutathiolation allows for reversible regulation,
levels in organ systems that come in contact with the oxidant-rich
and therefore generalized protection, of sensitive proteins.
atmosphere, such as the cornea and the lung. One of the most
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Pathogenesis of Cystic Fibrosis 355
A disrupted systemic antioxidant shield leads to predictable total GSH within such cells may remain normal, but the
damage to lung tissue by oxidants. Oxidants directly harm sensi- GSH :GSSG ratio may become substantially decreased. Howev-
tive lung epithelia. In addition, they are able to inactivate er, immune system cells are among the class of cells that have
antiproteases, which then leads to increased elastase damage, channels redundant to the CFTR. With a growing extracellular
increased mucus secretion, and deranged immune signaling.[30-34] deficit, immune system cells may actually attempt to efflux GSH
Oxidants also adversely affect ciliary beat function in the lung, and to rectify that deficit. Furthermore, with the increasing oxidant
lung surfactant levels are diminished by the oxidant burden.[33] burden, immune system cells may use up their stores of GSH in
There is an increased production of chloramines, which further self-protection. Immune cells then become GSH deficient. All in
decreases epithelial integrity.[35-37] A higher oxidant burden also all, what the body senses in cystic fibrosis is that there is some
creates cell structure abnormalities, which may lead to impaired threat that is using up all of the GSH in oxidative reactions, even
cell function or even premature cell death.[38-53] In the lung, though that threat is nonexistent. What is really occurring in cystic
generalized bronchoconstriction can be another consequence of fibrosis is defective GSH efflux, but the body has no way of telling
decreased antioxidant functioning.[54] Damage to the epithelial the difference.
tissue of the lung also permits greater adhesion of pathogens.[55] The body responds by mobilizing itself to meet the nonexistent
Oxidants can also inactivate other parts of the GSH system, such threat. In short, it inflames. GSH deficiency in leukocytes causes
as GSH reductase and γ-glutamylcysteine transferase, both neces- increased release of oxidants such as hydrogen peroxide.[70] Cellu-
sary for cellular protection and proper redox functionality.[56-58] lar GSH deficiency causes increased transcription of nuclear fac-
Protein S-glutathiolation will decrease, resulting in irreversible tor-κB, which then codes for greater levels of inflammatory
loss of sensitive protein function.[29] cytokines, such as tumor necrosis factor-α, activator protein-1,
A second consequence of impaired GSH efflux is increased monocyte chemoattractant protein-1, IL-8, and IL-1a.[71-85] Such a
viscosity of mucus. GSH plays an important role in mucolysis of cytokine profile creates inflammation and recruitment of neutro-
disulfide bonds in mucus, in much the same manner as the more phils and macrophages even in the absence of a threat, which is
well known cysteine donors such as N-acetylcysteine (NAC).[59] precisely what occurs in cystic fibrosis. (Of course, when a patho-
Increased viscosity of mucus has important consequences to the gen threat does present itself, the inflammation becomes even
lung environment.[59-67] more excessive.) As long as full GSH replenishment cannot occur
(because of defective GSH efflux from most of the cells of the
Finally, the redox system of GSH, as indicated by the
body), the inflammation will continue and become chronic, as it is
GSH :GSSG ratio manifesting redox potential, is an important
in cystic fibrosis.
immune system signal. The GSH :GSSG ratio is usually greater
than 9 :1, sometimes reaching over 100–200 :1, depending on the In addition to chronic inflammation, the continuing inability to
compartment. When that ratio is substantially decreased or there is replenish GSH, especially in immune cells, creates a situation of
a decrease in total GSH (GSH + GSSG), the body appears to immune incompetence. GSH deficiency in leukocytes causes, in
interpret such events as a call for assistance from the immune general, impaired release of lysosomal enzymes, decreased phago-
system to cope with some threatening challenge that is resulting in cytosis, and premature apoptosis.[70,86-100] GSH deficiency also
pathologic oxidative reactions that are outpacing GSH replenish- creates a situation of incomplete immune system signaling, be-
ment. For example, Day and colleagues[68,69] have found that when cause GSH reduction of disulfide bonds is necessary for such
normal mouse lung tissue is challenged with Pseudomonas aerugi- signaling. For example, antigen-presenting cells use the reductive
nosa, there is a 3-fold induction in epithelial lining fluid (ELF) power of GSH to present antigens to T cells.[101-104] B cells appear
GSH levels and a 2-fold induction in CFTR levels, presumably to similarly affected,[105,106] and activation of T and B cells appears
offset increased oxidative reactions. The inability to effect this related to GSH levels.[107-112] Interferon-γ signaling is also depen-
large increase in ELF GSH because of ineffectual transport due to dent on the presence of GSH.[113] Such interruptions of appropriate
CFTR mutation will substantially alter both the redox ratio and the immune signaling begin to shift the organism to a more T helper-2
level of total GSH. type of response, which is less effective in pathogen clear-
It is important to understand how the body reads the effects of ing.[101,107,114-118] In addition, GSH is necessary to create a reservoir
CFTR absence or malfunction on the GSH system. Cells without of nitric oxide (NO) [via creation of s-nitrosoglutathione
channels redundant to CFTR, such as lung epithelia (whose chan- (GSNO)], and the lack of such a reservoir leads to a generalized
nels redundant to the CFTR are at the basolateral, not the apical, lack of NO itself in the lung environment.[119-130] NO not only has
surface), will not be able to export GSH to the extracellular milieu, important bactericidal properties but also is necessary in cell
and the extracellular deficit may become quite severe. Levels of signaling and smooth muscle relaxation and helps regulate ciliary
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356 Hudson
beat function.[131-137] When antioxidant defenses are compromised, 2.1 Effect of Cystic Fibrosis Transmembrane Regulator
superoxide anion will scavenge NO almost instantaneously, the Mutation on Efflux of GSH
reaction limited only by the extent of diffusion. The depletion of
NO has important consequences for both lung function and im- In retrospect, it was the work of Linsdell and Hanrahan[138] that
mune function. first identified that the CFTR channel played a role in the efflux of
In short, then, a generalized GSH deficiency will cause inflam- GSH. Afer clamping the CFTR channels of Chinese hamster ovary
mation coupled, paradoxically, with decreased immune system cells, Linsdell and Hanrahan[138] compiled a list of substances that
competence to clear pathogens. These effects are in addition to the were subsequently not effluxed. GSH was on the list. Since that
loss of antioxidant protection and mucolytic activity noted above study published in 1998, however, it was the work of Gao and
in connection with GSH deficiency. The CFTR mutations that colleagues[139] that arguably pushed that insight further. Using cell
cause cystic fibrosis produce these consequences as a result of lines of cystic fibrosis lung epithelia, this team was able to
severely impaired efflux of GSH from most cells of the body. demonstrate markedly decreased GSH efflux. Velsor and col-
Figure 1 represents a summary of how diminished GSH transport leagues[140] and Day and colleagues[69] also found a 50% reduction
influences the pathophysiology of cystic fibrosis. in GSH levels in the ELF of the lung in uninfected CFTR knockout
mice and a lack of normal induction of GSH in the ELF when
2. GSH System Dysfunction in Cystic Fibrosis challenged by P. aeruginosa. Kogan and colleagues[141,142] found
The evidence for a primary GSH system dysfunction in cystic this same diminished GSH efflux with a variety of CFTR mutants,
fibrosis is steadily growing. including G551D, R347D, K464A, and K1250A, and through the
use of sophisticated tests were able to confirm that purified CFTR
protein alone directly mediated nucleotide-dependent GSH flux
and not via other associated chloride transport proteins.[142] Finder
et al.[143] also document a 49% reduction of GSH in bronchoalveo-
lar lavage fluid from cystic patients with fibrosis. The findings
Oxidant injury is unchecked, and
chronic inflammation begins
Leukocytes are drawn into the airways, and
GSH leaks out of the PMNs through MRP
Mucous thickens
Leukocytes are then depleted of intracellular GSH
necessary for phagocytosis,
oxidative burst, and other normal function.
This leads to premature apoptosis
Weakened immunity results in
colonization of bacteria
Chronic infection and inflammation results in increased
elastase activity and destruction of lung structures;
bronchiectesis develops
S-Glutathiolation
impaired
GSH-depleted
leukocytes transcribe
NF-κB, amplifying
inflammatory cascade
Preserved epithelial
intracellular GSH
impairs apoptosis
of infected lung
epithelium
Other antioxidants
are depleted
Extracellularly, total GSH and GSH/GSSG ratios are abnormally low
Defective CFTR protein in membrane does not allow
normal egress of GSH from lung epithelial cells
Fig. 1. The influence of diminished glutathione transport on the pathophysiology of cystic fibrosis. CFTR = cystic fibrosis transmembrane regulator; GSH =
glutathione; GSSG = glutathione disulfide; MRP = multidrug resistance-associated protein; NF-κB = nuclear transcription factor κB; PMN =
pol
y
morphonuclear leukoc
y
te.
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Pathogenesis of Cystic Fibrosis 357
from these five research teams constitute the ‘smoking gun’: cystic found substantially lower levels of GSH in sputum neutrophils
fibrosis directly causes significantly impaired GSH efflux. from patients with cystic fibrosis compared with blood neutro-
phils, which also correlated with cell death rates. Furthermore, in
this compartment, alterations in the expression of channels redun-
2.2 GSH Deficiency in the Cystic Fibrosis dant to the CFTR have also been noted: for example, multidrug
Lung Environment resistance-associated protein 1 has been shown to be upregulated
in cystic fibrosis erythrocytes.[150]
If we conceive of three distinct compartments in the cystic
fibrosis lung environment, we find empirical evidence that GSH 2.3 Related Phenomena
deficiency arises in the two compartments where the deficiency
would be expected if a transport abnormality were at fault. The As part of this hypothesis of mutation-derived GSH efflux
three compartments to visualize are: (i) cells that do not have a impairment, we should find that, other than the effects of the
channel redundant to the CFTR (at least at the apical surface), such mutation, the rest of the GSH antioxidant system remains intact in
as the epithelium of the lung; (ii) the extracellular milieu, com- patients with cystic fibrosis. This is in fact the case: at least normal
posed primarily of the lung ELF; and (iii) cells that do have levels of GSH peroxidase and γ-glutamylcysteine synthetase and
channels redundant to the CFTR (such as leukocytes or erythro- increased levels of γ-glutamylcysteine transferase, γ-glutamyl
cytes). transpeptidase, and GSH reductase have been found in patients
Gao and colleagues[139] found normal levels of total GSH in the with cystic fibrosis.[17,144,148,151-153] Therefore, the observed GSH
first compartment, which included cystic fibrosis lung epithelial deficiency is a primary deficiency not caused by malfunctions in
cells that did not have a channel redundant to the CFTR (at least at other parts of the overall GSH antioxidant system.
the apical surface). This should be expected, as there is no GSH
synthesis defect in cystic fibrosis as there is, say, in AIDS. The 2.4 Impaired GSH Efflux and Cystic Fibrosis Pathology
GSH :GSSG ratio in these cells was not ascertained and remains
to be analyzed. Note that the lack of ability to be depleted of GSH Many of the effects that would be expected from impaired GSH
may lead to decreased levels of appropriate apoptosis when these efflux in most cells have been noted as part of cystic fibrosis
cells are infiltrated by pathogens. pathology.
In the second compartment, consisting of ELF, several studies Inflammation in the absence of pathogen challenge has been
have found progressive GSH deficiency arising and persisting noted in the youngest of infants with cystic fibrosis.[1,2,154-157]
over time in patients with cystic fibrosis. Hull et al.[144] found that Other antioxidant systems of the body have been found to be
non-infected cystic fibrosis do not appear to have a GSH deficien- compromised in cystic fibrosis. This is in part a result of fat
cy in their ELF, though only the total GSH, and not the malabsorption due to pancreatic insufficiency in most patients
GSH :GSSG ratio, was analyzed. An altered GSH :GSSG ratio in with cystic fibrosis, resulting in lower levels of retinol and
the ELF of infants with cystic fibrosis would be evidence that the tocopherol, but this situation can be accelerated and aggravated by
impaired GSH efflux has begun to have an impact in the respirato- GSH deficiency. Affected systems include at least retinol, beta-
ry system of these patients.[145,146] Hull et al.[144] did find that carotene, tocopherol, activity of GSH peroxidase, ascorbic acid,
infected infants with cystic fibrosis infants had slightly lower total and activity of superoxide dismutase.[17,158-163] Antiproteases have
levels of GSH in their ELF. Brown et al.[147] determined that, been shown to be neutralized in cystic fibrosis, and surfactant
beyond infancy, plasma sulfhydryls decreased significantly with levels are lower.[164,165] There is an altered cytokine profile conso-
age in patients with cystic fibrosis. Roum et al.[148] found a nant with GSH deficiency, and also exhaled NO is not elevated, as
profound deficiency of GSH in the ELF in adult patients with it is in other respiratory diseases with a high oxidant bur-
cystic fibrosis, with levels of 5–10% of normal when oxidant den.[1-8,166-178] Interestingly, in vitro, the addition of S-nitrosogluta-
burden was factored in. This team also found plasma GSH levels thione to delF508 cystic fibrosis cell lines has been shown to help
of about 50% of normal in these adult patients with cystic fibrosis; in the maturation and functionality of the mutated protein.[179,180]
in both the ELF and plasma, they also found an extremely de- Furthermore, decreased apoptosis has been noted in pathogen-
creased GSH :GSSG ratio. Finder et al.[143] found a 49% reduction infiltrated cells without redundant anion channels in cystic fibro-
of GSH in bronchoalveolar lavage fluid from patients with cystic sis.[181]
fibrosis. In conclusion, the view that CFTR acts as an important GSH
In the third compartment, including cells with channels redun- efflux channel is gaining strength through recent empirical re-
dant to the CFTR, in the lung environment, Tirouvanziam et al.[149] search findings. In addition to several ‘smoking guns’, the related
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358 Hudson
phenomena and effects that one would expect if cystic fibrosis indicators, including peak flow, and in compliance analysis,
caused GSH efflux impairment are also empirically demonstrable cough.
(figure 1). This evidence leads us to inquire about therapeutic The results of these two clinical trials of aerosolized buffered
implications. However, it is important to remember that cystic GSH are very promising and warrant larger, multicenter trials of
fibrosis pathophysiology is multifactorial, and rectification of longer duration.
GSH system dysfunction in patients with cystic fibrosis will not Oral administration of GSH is not to be overlooked. Previously,
eliminate all harmful effects of the disease. researchers could not agree on whether GSH was cleaved in the
digestive tract or taken up intact in the jejunum. Newer studies
seem to indicate the latter.[196-200] Furthermore, there is new and
3. Therapeutic Implications innovative research being conducted to create a novel peptide that
could serve as a GSH efflux for cystic fibrosis cells.[201] Finally,
The usual and most direct route to augment GSH levels is to intravenous GSH has been used as a treatment for radiation
provide a cysteine donor, such as NAC, to the patient. As cysteine poisoning, as well as for other diseases such as Parkinson dis-
is the rate-limiting amino acid for GSH synthesis, this route is ease.[183,202,203] Given that it is most likely that the lung is a net
generally effective in otherwise healthy individuals. However, as importer of circulating GSH, this route might bear further investi-
we have seen, GSH synthesis is not impaired in cystic fibrosis; the gation in the case of cystic fibrosis.
problem is in GSH efflux from the cells in which GSH is synthe- Other respiratory ailments are marked by a decrease in GSH in
sized. Nevertheless, Hosseini and colleagues[182] have used a cys- the ELF. Clinicians treating such illnesses may want to examine
teine-rich whey powder to treat C57B1/6 mice infected with GSH augmentation in diseases such as adult respiratory distress
Pseudomonas spp. and noted some improvement in mortality; syndrome (ARDS), COPD, idiopathic interstitial pneumonia, IPF
therefore, precursors might usefully complement a strategy of of nonsmokers, idiopathic respiratory distress syndrome, and dif-
exogenous GSH augmentation. fuse fibrosing alveolitis.
Direct augmentation of GSH levels in the ELF with aerosolized In summary, augmentation of GSH in the ELF is feasible and
GSH has been carried out in vivo, including in patients with cystic may be useful not only for cystic fibrosis, but also for several other
fibrosis, AIDS, idiopathic pulmonary fibrosis (IPF), COPD, and respiratory conditions. Given the vasodilatory and anti-inflam-
other diseases.[183-191] Unfortunately, GSH in solution has a pH of matory properties of GSH, there may be contraindications to its
2.7 and is an irritant to the lung. This has hampered the usefulness use. It could be speculated that in patients with a history of
of this therapy for patients with respiratory ailments. Two clinical hemoptysis/pneumothorax, those yielding a positive culture for
trials, using buffered GSH with a pH of 5–6, have been carried out Burkholderia cepacia, or those with an FEV1 <30% predicted, the
in patients with cystic fibrosis. use of GSH may be contraindicated until further, more extensive
In the first trial, using the AKITA1 inhalation device, Griese trials have been conducted.
et al.[192] were able to increase the GSH level in bronchoalveolar
lavage fluid in patients with cystic fibrosis through inhalation of a 4. Conclusion
buffered GSH solution. One hour after inhalation, GSH levels
increased 3- to 4-fold, and at 12 hours levels of GSH were still In conclusion, new research is beginning to alter our under-
almost double those at baseline. Griese et al. found that with 14 standing of the CFTR channel. It is no longer possible to view it
days’ use of three times daily buffered GSH 300–450mg, FEV1merely or even primarily as a chloride efflux channel. At this point
and FVC increased an average of 6–7% over baseline (p < in time, it must be viewed as a chloride/GSH/bicarbonate channel,
0.001).[193] No change in oxidative markers was observed, though though this list may grow in the future. As we more fully under-
this might be because of the short duration of therapy. stand the nature and functions of the CFTR channel, new therapeu-
tic approaches will begin to come into view, as we have seen with
The second study carried out by Bishop et al.[194,195] was a
GSH. In one respect, cystic fibrosis may be viewed (at least in
randomized, double-blind, placebo-controlled trial. The dosage of
part) as the first identified disease with GSH transport dysfunction.
buffered GSH was 66 mg/kg/day, divided into four inhalation
sessions over a 6-week period. Results indicated that 11 of 13 Clinicians may be able to make effective use of these new
clinical indicators examined favored the GSH treatment group insights from cutting-edge research. However, it is important to
over the placebo group, including lung function scores, and statis- remember that the pathophysiology of cystic fibrosis is multifacto-
tical significance was achieved in improvement in several of the rial, and rectification of GSH system dysfunction in cystic fibrosis
1The use of trade names is for product identification purposes only and does not imply endorsement.
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Pathogenesis of Cystic Fibrosis 359
15. Jayaraman S, Song Y, Verkman AS. Airway surface liquid pH regulation in well-
patients will not eliminate all harmful effects of the disease. differentiated airway epithelial cell cultures and mouse trachea. Am J Physiol
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16. Hudson VM. Rethinking cystic fibrosis pathology: the critical role of abnormal
patients with cystic fibrosis are already using GSH and/or NAC reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic
without the physician’s knowledge.[204] Clinicians should inquire Biol Med 2001; 30 (12): 1440-61
from their patients with cystic fibrosis if they are already using 17. Benabdeslam H, Abidi H, Garcia I, et al. Lipid peroxidation and antioxidant
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(GSH) to patients with cystic fibrosis (CF) increases alveolar GSH concentra-
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