Biomedical Engineering Reference
In-Depth Information
of ROS, which could also inactivate
a
1
-l-AT in vitro (21). However, most of
the
a
1
-1-AT in the airspaces in cigarette smokers remains active and is there-
fore still capable of protecting against the increased protease burden. In
addition, the original observation that oxidation of
a
1
-1-AT occurs in
bronchoalveolar lavage in smokers has not been confirmed (52).
B. Mucus Hypersecretion
Chronic bronchitis is associated with hyperplasia of both epithelial goblet
cells and submucosal glands in the airways. Mucins, which are complex gly-
coproteins that provide the viscoelastic properties of mucus, are an essential
protective mechanism in the upper airways. The regulation of mucins is
altered in the lungs of COPD patients. The airways of smokers contain more
goblet cells than do those of non-smokers and goblet-cell activation results
in mucus hypersecretion leading to airway plugging. Cigarette smoke can
activate epidermal growth factor (EGF) receptors by tyrosine phosphoryla-
tion, resulting in the induction of mucin (MUC5AC gene expression) synth-
esis in epithelial cells and in vivo in lungs (53). Selective EGFR typrosine
kinase inhibitors and antioxidants inhibited the cigarette smoke-mediated
MUC5AC gene expression suggesting the role of ROS in the gene expres-
sion (53). 4-HNE have been shown to cause the release of mucus from air-
way epithelial cells and fibroblast by the activation of ERK1
=
2 (54).
It has also been shown that elastase released from neutrophils impairs
mucociliary clearance and stimulates goblet cell metaplasia and mucin
production. Neutrophil elastase increases the expression of MUC5AC, by
enhancing mRNA stability (55). Understanding of the EGF receptor signal-
ing pathway in cigarette smoke-mediated upregulation of mucin gene
expression could lead to targeted inhibition of mucus hyper-production in
epithelial cells.
C. Remodeling of Extracellular Matrix
Oxidative stress has been shown to be involved in the remodeling of extra-
cellular matrix in lung injury. Treatment of cigarette smoke to alveolar
macrophages obtained from patients with COPD release increased amounts
of MMP-9 compared to that of smokers suggesting the role of oxidative
component of CS in increased elastolytic enzyme by alveolar macrophages
of only patients with COPD (56). It has been shown that the oxidative stress
caused by ozone and lipid peroxides induce matrix protein type I collagen
and MMP-1 gene expression (57). Other forms of oxidative stress derived
from tert-butyl hydroperoxide and iron can also modify collagen synthesis,
by a mechanism presumably involving redox sensor
=
receptor. Recent study
by Wang et al. (58) has shown that cigarette smoke produces airway wall
remodeling in rat
tracheal explants by induction of procollagen and
