Biomedical Engineering Reference
In-Depth Information
function to activate other proteins similar to a distant relative, interleukin-
converting enzyme. Cathepsin C or dipeptidyl peptidase I has limited extra-
cellular matrix degrading activity but is required for activation of nearly all
matrix degrading serine proteinase pro-enzymes to their active form. Cathe-
psins L and S have large active pockets with relatively indiscriminate sub-
strate specificities that include elastin and other matrix components. These
enzyme have an acidic pH optima but cathepsin S retains
25% of its elas-
tolytic capacity at neutral pH (making it approximately equal to NE).
Cathepsin K is a potent elastase predominantly expressed in osteoclasts
but also by macrophages in the vasculature and perhaps other tissues. Thus,
these enzymes clearly have the capacity to cause lung destruction when tar-
geted to the cell surface or extracellular space particularly in acidic microen-
vironments.
Cystatins:
Cystatins represent families of cysteine proteinase inhibi-
tors, some of which are strictly intracellular, while others, such as cystatin
C, possess a signal peptide and are secreted by a variety of cells into the
extracellular fluid. Cystatin C, comprised of a single non-glycosylated 120
amino acid peptide chain (13 kDa), forms reversible 1:1 complexes with
enzymes in competition with substrates. Cystatin C is the most ubiquitous
cystatin found in all human tissues and body fluids tested, providing general
protection against tissue destruction by intracellular cathepsin enzymes
leaking from dying cells. It is also a product of alveolar macrophages.
III. EVIDENCE FOR ROLE OF PROTEINASES IN EMPHYSEMA
A. Human Data
The older literature contains studies that either support, e.g. Refs. 13, 14, or
refute, e.g. Ref. 15, an association of NE with COPD. Evidence supporting a
role for NE include: (1) the presence of HNE and neutrophils in the lung
tissue and BAL of patients with emphysema in some (but not all) studies,
(2) smoking leads to an acute increase in a specific peptide released by
HNE action on fibrinogen, and (3) cigarette smoke can oxidize a methionine
residue in the reactive center of
a
1
-AT, inactivating
a
1
-AT, and thus altering
the HNE:
a
1
-AT balance. Whether this inactivation occurs in vivo is uncer-
tain. The strongest evidence for the role of NE in COPD comes from the
fact that patients with
a
1
-AT deficiency are at increased risk of emphysema.
With respect to MMPs, correlative studies in human emphysematous
lung tissue have demonstrated the presence of MMPs-1, -2, MT-1MMP
(16). As mentioned, cultured macrophages found a correlation between
MMP-1 and MMP-9 in smokers with emphysema as opposed to smokers
without emphysema (10). This study suggests that expression of certain
MMPs might predict those smokers susceptible to emphysema.
