Biomedical Engineering Reference
In-Depth Information
abrogated by the antioxidant glutathione (GSH) in concentrations (500
m
M),
which are present in the epithelial lining fluid. Extra- and intra-cellular glu-
tathione appears to be critical to the maintenance of epithelial integrity
following exposure to cigarette smoke. Studies have demonstrated that the
increased epithelial permeability of epithelial cell monolayers in vitro and
in rat lungs in vivo following exposure to cigarette smoke condensate was
associated with profound changes in the antioxidant glutathione (2,44).
Furthermore, depletion of lung GSH alone, by treatment with the
glutathione synthesis inhibitor buthionine sulfoximine, induces increased
airspace epithelial permeability both in vitro and in vivo (2).
XII. NEUTROPHIL SEQUESTRATION AND MIGRATION IN
THE LUNGS
The inflammatory response in the airspaces in COPD is characterized by the
influx of leukocytes of which polymorphonuclear leukocytes are the promi-
nent cells. The recruitment of neutrophils to the airspaces is initiated by
the sequestration of these cells in the lung microcirculation. Sequestration
of neutrophils in the pulmonary capillaries permits cell interaction with
the pulmonary capillary endothelium, resulting in their adherence to the
endothelium and thereafter their transmigration across the alveolar capillary
membrane to the interstitium and airspaces of the lungs in response to
inflammation or infection.
Neutrophils can be activated while in transit in the pulmonary microcir-
culation by a number of mediators, including cytokines released from resident
lung cells, alveolar macrophages, epithelial and endothelial cells. Inhaled oxi-
dants such as those contained in cigarette smoke and other air pollutants
could influence the transit of cells in the pulmonary capillary bed by decreas-
ing the neutrophil deformability (in order neutrophil to pass the smaller capil-
lary segments). Studies in man using radio-labeled neutrophils and red cells
show a transient increase in neutrophil sequestration and decreased neutro-
phil deformability in the lungs during smoking
=
oxidative stress (1), which
returns to normal upon cessation of smoking. A similar decrease in deform-
ability can be demonstrated in vivo for neutrophils from the blood of subjects
who are actively smoking (1). Support for oxidative stress-mediated decreased
neutrophil dormability comes from in vitro studies, which show that the
decreased neutrophil deformability induced by cigarette smoke exposure is
abolished by antioxidants, such as glutathione (21).
Neutrophils sequestered in the pulmonary microcirculation will subse-
quently respond to chemotactic components in cigarette smoke and become
more adhesive to pulmonary vascular endothelial cells, in preparation for
migration into the airspaces. Smoke exposure in humans results in increased
levels of chemotactic factors in the airspaces. Studies in animal models of
