Biomedical Engineering Reference
In-Depth Information
resulted in increased ELF AAT levels and antielastase capacity (125). In
addition, rAAT could be detected in the serum of these individuals, indicat-
ing that the lower respiratory tract epithelium is permeable to rAAT and
that rAAT provides antiprotease protection for the interstitium of the lung,
as well as the epithelial surface. However, the use of rAAT in augmentation
trials has been limited and alternative sources of glycosylated AAT, which
will be more stable than the nonglycosylated AAT, are now being produced
in transgenic animals, and the results of these studies are expected soon.
Recombinant SLPI (rSLPI) has also been administered to individuals
with CF resulting in decreased active NE and decreased IL-8 levels on the
epithelial surface of the lung. The latter effect is partly due to the ability
of SLPI (as well as AAT) to inhibit NE-induced upregulation of IL-8 by
the respiratory epithelium (126-128). Pharmacokinetics of aerosolized
rSLPI show that although SLPI levels and antielastase capacity are in-
creased in the ELF of CF patients and healthy control postaerosolization,
rSLPI did not accumulate on the respiratory epithelial surface (127).
Although the administration of SLPI and AAT may prove useful in
neutralizing serine protease activity in neutrophil-dominated lung diseases,
they may have little effect on the other nonserine proteases present on the
epithelial surface. The old paradigm of emphysema, being due to unopposed
activity of NE, is no longer the full explanation, and in COPD, a condition
characterized by significantly increased numbers of alveolar macrophages,
with resultant elevated cathepsin and MMP activity, and by a combined
antiprotease therapeutic strategy using cystatins and TIMPs, as well as
AAT or SLPI, may prove to be the most useful way to combat protease-
mediated lung destruction.
REFERENCES
1. Long GL, Chandra T, Woo SL, Davie EW, Kurachi K. Complete sequence
of the cDNA for human alpha 1-antitrypsin and the gene for the S variant.
Biochemistry 1984; 23:4828-4837.
2. Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin
deficiency. Am J Med 1988; 84:13-31.
3. Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, Holmes MD.
The alpha 1-antitrypsin gene and its mutations. Clinical consequences and
strategies for therapy. Chest 1989; 95:196-208.
4. Travis J, Salvesen GS. Human plasma proteinase inhibitors. Annu Rev
Biochem 1983; 52:655-709.
5. Mornex JF, Chytil-Weir A, Martinet Y, Courtney M, LeCocq JP, Crystal RG.
Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal
and alpha-1-antitrypsin-deficient individuals. J Clin Invest 1986; 77:1952-1961.
6. du Bois RM, Bernaudin JF, Paakko P, et al. Human neutrophils express the
alpha 1-antitrypsin gene and produce alpha 1-antitrypsin. Blood 1991; 77:
2724-2730.
