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Glutathione Articles - Cystic Fibrosis
New Insights Into the Pathogenesis of Cystic Fibrosis:
Pivotal Role of Glutathione System Dysfunction and Implications for
Therapy
Valerie M. Hudson, PhD
Treat Respir Med 2004; 3 (6):353-363
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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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