Biomedical Engineering Reference
In-Depth Information
C. Antioxidant and Stress Response Genes
An important effect of oxidative stress in the lungs is the upregulation of
protective antioxidant and stress response genes. Human studies have
shown elevated levels of glutathione in epithelial lining fluid in chronic cigar-
ette smokers compared with non-smokers (14,45). This increased level of
glutathione is due to transcriptional upregulation of the gene for GSH
synthesis (
g
-GCS) by components within cigarette smoke in epithelial cells
(43,44). Thus oxidative stress, including that produced by cigarette smoking,
causes upregulation of the gene involved in the synthesis of glutathione as a
protective mechanism against oxidative stress. However, the injurious
effects of cigarette smoke may occur repeatedly during and immediately
after cigarette smoking when the lung is depleted of antioxidants, including
glutathione.
The cytokine tumor necrosis factor (TNF), which is present as part of
the airway inflammation in COPD, has been shown to increase
g
GCS
mRNA expression in alveolar epithelial cells (93). Corticosteroids have been
used as anti-inflammatory agents in COPD, but there is still doubt over their
effectiveness in reducing airway inflammation in COPD. Interestingly dexa-
methasone also causes a decrease in intracellular glutathione in airspace
epithelial cells, by downregulating the GSH biosynthesis (93). Moreover,
the induction of
g
GCS produced by TNF-
a
in epithelial cells is prevented
by co-treatment with dexamethasone (93). These effects may have relevance
for the treatment of COPD patients with corticosteroids. Transforming
growth factor (TGF-
b
1
) has been shown to decrease antioxidant glutathione
synthesis and is associated with increased ROS production in human alveo-
lar epithelial cells and pulmonary artery endothelial cells in vitro (94).
Increased TGF-
b
1
expression was associated with fibrosis in the basement
membrane in the lungs and depletion of GSH, suggesting that cigarette
smoking interferes in normal repair (Fig. 13).
The activities of SOD and glutathione peroxidase (GP
X
), manganese
superoxide dismutase (MnSOD), and metallothionein (MT) have been
shown to be higher in the lungs of rats exposed to cigarette smoke (95). Simi-
larly, antioxidant enzyme activities were enhanced in alveolar macrophages
in hamsters following cigarette smoke exposure, which resulted in reduced
mortality when the animals were subsequently exposed to
>
95% oxygen
(1). It is likely that alveolar macrophages undergo an adaptive response to
chronic oxidant exposure that may ameliorate potential damage to lung cells
from further oxidant stress by induction of antioxidant enzymes.
Extracellular glutathione peroxidase (eGPx) is an important antioxi-
dant in the lungs and may be secreted by epithelial cells and macrophages,
particularly in response to cigarette smoke or oxidative stress (96). Ishii et al.
(97) have shown that glutathione-S-transferase PI (GSTP1) acts as a
protective enzyme against cigarette smoke in the airway cells. Similarly,
