Biomedical Engineering Reference
In-Depth Information
AAT active site residues by oxidants in cigarette smoke may partially
explain the development of protease-mediated lung damage in non-
AAT deficient individuals. Other mechanisms may also be important.
For example, oxidation of AAT can be reversed by the enzyme methio-
nine sulfoxide reductase (Msr), although little is known about the activity
of Msr in the lung (24). Proteolytic cleavage of AAT and the other sig-
nificant antiprotease, SLPI, may also be important (25). Alterations in
the levels of proteases (cathepsins, MMPs, serine proteases) or protease
inhibitors (SLPI, elafin, TIMPs, cystatins) due to polymorphisms in the
gene coding for these proteins may be responsible for alterations in
protease:antiprotease levels in the lung which may predispose some, but
not all smokers, to the development of COPD (26,27). However, research
in the area of polymorphisms and lung disease is still in its infancy,
and therefore, it is too early to tell whether this field will uncover new
information to help explain the development of COPD in some smokers
but not others.
e. Other Functions
Alpha-antitrypsin has a wider role to play in inflammation resolution than
simply as an inhibitor of serine proteases (Fig. 1). In this regard, it appears
that AAT may play an important part as an anti-inflammatory protein,
regulating the proinflammatory effects of NE and other proteases (28).
Neutrophil elastase has been shown to induce IL-8 release from epithelial
cells (29). Inhibition of NE by AAT may therefore be important in
preventing neutrophil recruitment and preventing an ongoing cycle of
inflammation. Alpha-antitrypsin can regulate the NE cleavage of the phos-
phatidylserine receptor (PSR), a macrophage cell surface protein, which is
crucial in clearance of apoptotic neutrophils (30). The process of apoptotic
neutrophil clearance is important in the context of inflammation resolu-
tion. Alpha-antitrypsin has also been demonstrated to inhibit the cytotoxic
effects of alpha-defensins by blocking defensin-induced IL-8 production by
epithelial cells (31). Plasma-purified AAT can suppress Pseudomonas
colonization in a model of chronic lung infection (32). One of the primary
reasons for this may be related to improved opsonization and removal of
Pseudomonas by phagocytosis, a process that is hindered by the action of
free NE (33). Alpha-antitrypsin may also play an important role in inhibit-
ing the proinflammatory effects of proteinase 3, which has a central role in
the pathogenesis of Wegener's Granulomatosis (34). Therefore, given the
multiple deleterious effects of a chronic burden of NE in the lung which
includes connective tissue degradation, increased IL-8 production,
decreased bacterial clearance and impaired apoptotic cell removal, the
use of AAT in the treatment of chronic lung disease may be therapeuti-
cally relevant in the near future.
