Biomedical Engineering Reference
In-Depth Information
conserved His, Asp, and Ser residues that form a charge relay system that
functions by transfer of electrons from the carboxyl group of Asp to the
oxygen of Ser which then becomes a powerful nucleophile able to attack
the carbonyl carbon atom of the peptide bond of the substrate. The enzymes
are synthesized as pre-proenzymes in the endoplasmic reticulum and pro-
cessed by cleavage of the signal peptide (pre-) and removal of a dipeptide
(pro-) by dipeptidylpeptidase I, and stored in granules as active packaged
proteins. These serine proteinases are expressed in a lineage-restricted and
developmentally specific manner. For example, neutrophil elastase, protei-
nase 3, and cathepsin G and their granules are formed during a very specific
stage during the development of myeloid cells. Mature neutrophils contain
serine proteinases, but they do not have the capacity to transcribe new pro-
teinases in response to environmental stimuli. Upon neutrophil activation, a
portion of NE and other azuriphil constituents translocate to the cell sur-
face, but only a small fraction is released from the cell. Cell surface expres-
sion serves to focus proteolysis. Interestingly, surface-bound NE is unable to
be completely inhibited by
a
l
AT.
1. Neutrophil Elastase
Neutrophil elastase (NE) has activity against a broad range of extracellular
matrix proteins including elastin. Following the discovery of
a
1
-AT defi-
ciency and the capacity of HNE to cause emphysema in experimental ani-
mals, NE has been considered to be of primary importance in the
pathogenesis of pulmonary emphysema (see evidence below). The main roles
of NE in COPD are thought to be to destroy lung elastin and act as a secre-
tagogue. In addition, NE is involved in monoctye transvascular migration,
and in some instances mediates neutrophil migration. However, it has been
difficult to prove that NE, or any other proteinase for that matter, promotes
neutrophil migration by proteolytically creating paths of degraded matrix.
Despite long-term interest in NE and development of NE inhibitors, these
inhibitors remain largely untested in COPD.
2. Proteinase 3
Proteinase 3 (PR3) is roughly 40% as potent as HNE against elastin. PR3
has been shown to cause emphysema in experimental animals (3). This mole-
cule has been identified as the autoantigen target of cytoplasmic-staining
anti-PMN autoantibody in Wegener's granulomatosis.
3. CathepsinG
Cathepsin G (CG) is stored in neutrophil primary granules and to a lesser
degree in mast cells and a subset of peripheral blood monocytes. CG is a
chymotryptic serine proteinase with capacity to degrade ECM components.
CG has 20% of the elastolytic capacity of HNE.
