Biomedical Engineering Reference
In-Depth Information
NF-
k
B activation via an ROS-dependent mechanism. They suggested that
transactivation of EGFR, rather than MAPK activation, was involved in
airway remodeling. Furthermore, the cigarette smoke-mediated activation
of EGFR was oxidant-dependent.
D. Apoptosis
Apoptosis, or programmed cell death, is a physiological program for removal
of harmful or unwanted cells in vivo leading to resolution of inflammation.
Recently, it has been proposed that apoptosis of alveolar wall cells occurs
in response to cigarette smoking, resulting in progressive cell loss and
emphysema. Oxidative stress has been implicated in mediating apoptotic
processes, particularly in airway epithelial cells. Recent evidence from both
in vitro and in vivo studies in animals and in man has shown that apop-
tosis occurs in smoke exposed macrophages, airway epithelial, dendritic
cells, and lung fibroblasts (59,60). This may be due to activation of cas-
pases and
=
or apoptosis signal-regulating kinase-1 which is held in an inac-
tive form by thioredoxin and when oxidized by ROS this triggers
apoptotic pathways (61). The cigarette smoke-mediated apoptosis was
inhibited by antioxidants such as glutathione and N-acetyl-l-cysteine treat-
ments (59,60). Recent reports have shown both in vivo and in vitro that
cigarette smoke exposure produces endothelial cell apoptosis (62-65) and
that pulmonary vascular endothelial cell apoptosis is present in emphyse-
matous lungs (62). Recently, Tuder et al. (66) have shown that inhibition
of KDR leads to increased oxidative stress which is mediated by reactive
carbonyls and aldehydes leading to emphysema. They have also showed
that both a caspase inhibitor (Z-Asp-CH2) and a superoxide dismutase
mimetic (M40419) blocked the development of emphysema and signifi-
cantly reduced lung markers of oxidative stress and apoptosis (65). In
addition, signaling and survival pathways involving AP-1, NF-
k
B, and
Akt and the downregulation of the vascular endothelial growth factor
receptor KDR (VEGF-KDR) have been proposed as part of the mechan-
ism (62,63). However, using a variety of cellular models, it is proposed
that cigarette smoke induces necrosis by inhibition of caspase activation
and hence it prevents apoptosis (67). Aoshiba et al. (68) have shown that
single intratracheal injection of active caspase-3 resulted in epithelial apop-
tosis and enhanced elastolytic activity in mice. Further confirmation of the
role of apoptosis in emphysematous changes in murine model was
described by intratracheal injection of nodularin, a proapoptotic seri-
ne
=
threonine kinase inhibitor. Surprisingly, this approach did not cause
inflammation or other forms of lung pathology, a hallmark of emphysema.
Nevertheless, it is clear that lung structural cells undergo apoptosis by
cigarette smoke but the scenario may be different for inflammatory cells.
It
is
likely that cigarette smoke and its constituents
through their
