Abstract
The major factor in the development of chronic obstructive airways disease (COPD)
is cigarette smoking, although not all smokers develop chronic obstructive
pulmonary disease. Inflammation and destruction has been shown in the lungs of
smokers with chronic obstructive pulmonary disease. Oxidative stress, both from
cigarette smoke and oxidants generated endogenously by cellular processes,
contribute to the inflammation that occurs in the lungs in chronic obstructive
pulmonary disease. It remains unclear why certain individuals appear susceptible to
the effects of cigarette smoke and go on to develop inflammation and airflow
limitation. The glutathione redox system is an important antioxidant protective
system within the lungs, and this system may play a critical role in the development
of inflammation. An alteration in the transcription of pro-inflammatory cytokines and
mediators is also likely to contribute to the inflammation within the lung. Nuclear
factor kappa-B (NF-kB) and activator protein-1 (AP-1) are both redox sensitive
transcription factors, and are involved in the regulation of the gene transcription of
many pro-inflammatory mediators. Activator protein-1 and nuclear factor kappa-B
have a close relationship with y-glutamylcysteine synthetase (y-GCS) (glutamate
cysteine ligase, GCL), the rate limiting enzyme in the synthesis of glutathione, with
the y-glutamylcysteine synthetase gene containing various elements including an
Activator protein-1 binding site. Susceptibility to the effects of cigarette smoke is
likely to explain why certain individuals develop chronic obstructive pulmonary
disease, and this susceptibility may arise from an earlier viral infection such as
adenoviral infection that lies dormant, but which in the face of an oxidant stimulus
such as cigarette smoke augments the inflammatory process.
The in vivo studies herein have examined glutathione and y-glutamylcysteine
synthetase, gene transcription, oxidant/antioxidant imbalance, the redox sensitive
transcription factors nuclear factor kappa-B and activator protein-1, and have assessed for the presence of the early one adenoviral protein in human lung in
smokers and patients with COPD.
The results show similar levels of total glutathione in the lungs of patients with and
without airflow obstruction, and decreased y-glutamylcysteine synthetase activity in
patients with severe airflow obstruction who have undergone lung volume reduction
surgery for emphysema compared to those with no airflow obstruction. Local lung
oxidative stress as measured by malondialdehyde, and trolox equivalant antioxidant
capacity a marker of systemic oxidative stress did not correlate with lung function.
DNA binding of Nuclear factor kappa-B correlated with lung function as measured
by percent predicted forced expiratory volume in one second (FEVi), however no
such relationship was found with Activator protein-1 DNA binding. Examination for
early one adenoviral gene and protein in human lung tissue failed to reveal
conclusive results.
In conclusion levels of glutathione in human lung tissue, oxidative stress including
both lung and systemic oxidative stress, and the DNA binding of activator protein-1
in lung are not related to the degree of airflow obstruction present.
