Biomedical Engineering Reference
In-Depth Information
of the herpes simplex virus type 1 (113). Finally, cathepsin B has been impli-
cated in the IL-8 mediated transactivation of the epidermal growth factor
receptor, an effect that can be inhibited by small synthetic inhibitor of cathe-
psin B (114). Therefore, cystatins may have an additional role in inhibiting
cell migration and chemotaxis in microvascular endothelial cells.
VII. THERAPEUTIC APPLICATIONS OF ANTIPROTEASES
IN LUNG DISEASE
A large variety of lung diseases are characterized by the presence of multiple
unopposed protease activities (serine protease, MMPs, and cathepsins).
Lung tissue is susceptible to the direct effect of proteolysis in addition to
its effect on other soluble host defense proteins present on the respiratory
surface. As lung tissue is susceptible to the direct and indirect effects of these
proteases, it would seem reasonable to hypothesize that antiprotease ther-
apy directed against these activities would be of benefit. Small synthetic
inhibitors based on the active sites of many of the naturally occurring
antiproteases are currently being tested in animal models of emphysema
(115-118). However, some of these inhibitors possess certain drawbacks—
decreased half-life, increased toxicity, and the induction of an immune
response—that may limit their use. In addition, many of these inhibitors
have not yet been tested on humans. Much of the clinical work in this area
has centered on the use of recombinant and plasma-purified versions of the
naturally occurring antiproteases, particularly AAT and SLPI. Clinical
trials have already been conducted using AAT and SLPI in CF and AAT
deficiency.
Alpha-antitrypsin augmentation therapy with plasma-purified AAT
has been available for the treatment of AAT deficiency since 1987. Intrave-
nous administration of plasma-purified AAT augments serum and lung
levels of AAT and increases antielastase capacity (119,120). There are new
emerging data to show that long-term AAT augmentation in AAT deficient
patient results in a less rapid decline in lung function, loss of lung tissue, and
decreased mortality in these individuals (121,122). However, the number of
individuals with AAT deficiency greatly exceeds the plasma available as a
source of AAT posing a problem with the use of plasma-purified AAT
(123). In addition, there are also fears concerning the use of plasma-purified
product, in general, regarding the transmission of infectious agents. In this
regard, recombinant AAT (rAAT) has been evaluated in augmentation
trials. Initial trials showed that intravenous administration of rAAT to
animals resulted in rapid renal clearance most likely due to the absence of
carbohydrate side chains, which stabilize the AAT structure, obviating its
use as an intravenous agent (124). As an alternative, aerosolized rAAT
was evaluated in AAT deficient patients. This route of administration
