Biomedical Engineering Reference
In-Depth Information
and thereby bind to NE. In the case of PPE, only Met358 appears to be
important for binding to, and inhibiting, this protease (16). The differences
in binding of oxidized AAT to NE and PPE can most likely be explained
by the previous observation that oxidized AAT is a much less potent inhibitor
of NE, although it will still bind and inhibit NE albeit at a much slower rate.
However, oxidized AAT does not inhibit PPE indicating that the inhibitory
mechanisms of AAT for PPE and NE are different (13,17).
c. AAT Deficiency
Alpha-antitrypsin deficiency is a lethal, hereditary disorder characterized by
liver disease and early-onset emphysema. The most common phenotype
associated with this condition is the Z variant of AAT (18). The Z mutation
occurs as a result of a single amino acid substitution (Glu
342
-Lys
342
), which
affects the secondary structure of AAT (2). This mutation destroys a salt
bridge and affects the secondary structure of AAT, a perturbation involving
a unique molecular interaction between the reactive center loop of one mole-
cule and the A sheet of another (19). This leads to polymerization of AAT
molecules resulting in accumulation of Z AAT polymers in the endoplasmic
reticulum of hepatocytes. The liver disease, in AAT deficiency, is thought to
result from the accumulation of Z AAT deposits in the hepatocyte (20).
Such Z AAT deposits in the liver result in the disruption of cell function
and integrity leading eventually to cell death (7). However, this results in
decreased circulating Z AAT leading to an increased risk for the develop-
ment of emphysema by the third or fourth decade of life (21). Early-onset
emphysema is believed to occur as a result of decreased levels of AAT in
the lung allowing greater and prolonged exposure to NE released from neu-
trophils. In addition, Z AAT is a less effective antiprotease than its wild-type
counterpart (22). It has been demonstrated recently that a significant por-
tion of the Z AAT present on the respiratory tract is polymerized,
a state in which Z AAT is inactive as an antiprotease and may act as
a neutrophil chemoattractant (23). Therefore, the fourfold problem of
lower levels, decreased activity, polymerization of Z AAT, and neutrophil
chemoattraction predisposes to emphysema in affected individuals. A
further complication associated with early-onset emphysema in AAT defi-
ciency is cigarette smoking. Owing to the large number of oxidants present
in cigarette smoke, together with increased oxidant released from activated
neutrophils, an even greater loss of Z AAT activity is thought to result from
this increased oxidant burden, and individuals with AAT deficiency who
smoke have demonstrably shortened life expectancy of
>
20 years (18).
d. Non-AAT Deficient Emphysema
The majority of patients with COPD have normal circulating concentra-
tions, especially lung concentrations, of AAT. However, oxidation of the
