Biomedical Engineering Reference
In-Depth Information
smoke exposure have shown increased neutrophil sequestration in the
pulmonary microcirculation, associated with upregulation of adhesion
molecules on the surface of these cells (1,21). Activation of neutrophils
sequestered in the pulmonary microvasculature could also induce the release
of ROS and proteases within the microenvironment with limited access for
free radical scavengers and antiproteases. Thus, destruction of the alveolar
wall, as occurs in emphysema, could result from a proteolytic or oxidant
insult from the intra-vascular space, without the need for the neutrophils
to migrate into the airspaces. Increased sequestration of neutrophils
also occurs in the pulmonary microcirculation during exacerbations of
COPD (1,21).
XIII. CONSEQUENCES OF OXIDANT
=
ANTIOXIDANT
IMBALANCE
A. Protease
=
Antiprotease Imbalance
The development of a protease
=
antiprotease imbalance in the lungs is a cen-
tral hypothesis in the pathogenesis of emphysema in smokers. This theory
was developed from studies of early onset emphysema in antitrypsin
(
a
1
-AT) deficient subjects. In the case of smokers with normal levels of
a
1
-AT, the elastase burden may be increased as a result of increased
recruitment of leukocytes to the lungs and there may be a functional defi-
ciency of
a
1
-AT, due to oxidative inactivation of
a
1
-AT in the lungs.
It is clear that an imbalance between an increased elastase burden in
the lungs and a functional ''deficiency'' of
a
1
-AT due to its inactivation
by oxidants is an over simplification since other proteinases and antiprotei-
nases are also likely to have a role. Early studies showed that the function of
a
1
-1-antitrypsin in bronchoalveolar lavage was decreased by around 40% in
smokers, compared with non-smokers (48). This ''functional
a
1
-l-AT defi-
ciency'' is thought to be due to inactivation of the
a
1
-1-AT by oxidation
of the methionine residue at its active site by oxidants in cigarette smoke.
Secretory leukoprotease inhibitor (SLPI), another major inhibitor of neutro-
phil elastase (NE), can also be inactivated by oxidants (49).
In vitro studies have also shown loss of
a
1
-l-AT inhibitory capacity
when treated with oxidants including cigarette smoke. In addition, oxida-
tion of the methionine residue in
a
1
-l-AT was confirmed in the lungs of
healthy smokers (50). Furthermore, neutrophilic inactivation of
a
1
-l-PI
may be caused by hypochlorous acid or peroxynitrite. It has been shown
that stimulated alveolar type II epithelial cells and alveolar macrophages
(but not fibroblasts) from guinea pigs inactivated
a
-l-PI in the presence of
myeloperoxidase (1,51). These studies supported the concept of inactivation
of
a
1
-l-AT by oxidation of the active site of the protein. As already dis-
cussed, macrophages from the lungs of smokers release increased amounts
