Proteinases in COPD - Chronic Obstructive Pulmonary Disease - page 328

Figure 1 Pathogenesis of COPD. Chronic exposure to cigarette smoke leads to
inflammation with subsequent release of proteinases including neutrophil elastase
(NE) and MMPs such as macrophage elastase (MMP-12) and gelatinase B (MMP-
9). Proteolytic destruction of extracellular matrix (ECM) coupled with inadequate
repair results in airspace enlargement or emphysema. Loss of ECM support can
result in cell death, alternatively, cigarette smoke and cellular production of oxidants
also can initiate cell death. Ultimately, one must lose both ECM and alveolar cells to
result in loss of alveolar units with coalescence into larger dysfunctional airspaces. In
addition, cigarette smoke has a myriad of effects on the airways including inflamma-
tion, mucus production, and subepithelial fibrosis resulting in small airway obstruc-
tion. Of note, MMP-9 may activate TGF- b resulting in this fibrotic component.

II. PROTEINASE CLASSES

There are four classes of proteinases, serine, cystene, aspartic, and metal
loproteinases that are distinguished by their mechanism of catalysis and
endogenous inhibitors. Serine proteinases, particularly NE, have been stu-
died most extensively in COPD. Recently, MMP activity has been appre-
ciated as potentially important in COPD. Cysteine proteinases are largely
intracellular, but they are potent and may be released from cells and thus
contribute to extracellular proteolysis in COPD. Aspartic proteinases are
intracellular enzymes that are generally not believed to contribute to COPD.

A. Serine Proteinases

The major serine proteinases implicated in COPD are neutrophil elastase
(NE), and perhaps two other enzymes that are also found in primary or
azuriphil granules of neutrophils, and to a small extent in monocyte (but
not macrophage) granules. These serine proteinases are characterized by