Biomedical Engineering Reference
In-Depth Information
solely by environmental factors (such as prolonged cigarette smoke expo-
sure), as only a proportion of smokers develop significant airflow obstruc-
tion, and so genetic factors must play a role (17). Neutrophil priming may
occur only in susceptible individuals, leading to increased neutrophil pool-
ing in the lung, increased degranulation, and therefore increased tissue
damage, although it remains unclear whether this is a predisposing factor
for COPD or a consequence of the disease.
VI. ACTIONS OF NEUTROPHIL PROTEASES IN VITRO AND IN
VIVO
A. The Actions of NE
Neutrophil elastase was the first serine proteinases to be shown to produce
emphysema in animal models and has been more extensively studied than
CG or PR3. Intratracheal instillation of purified NE induced emphysema in
dogs and hamsters (139-141), and intratracheal instillation of other elastases
have given similar results in various animal models—Papain (plant elastase)
in rats (142), neutrophil lysates in dogs (143), and porcine pancreatic elastase
in rats and hamsters (144,145). In fact, the development of emphysema is spe-
cific to elastase activity with emphysema severity relating proportionally to
the elastolytic potency of the elastase used (144,145), and in these models,
emphysema can be prevented by specific elastase inhibitors (146,147).
Free NE activity has been detected in secretions of patients with
COPD (66) and this is felt to be fundamental in the development of the con-
dition in vivo. Once at the site of tissue damage, neutrophils degranulate,
releasing enzymes into the liquid mileu or directly onto the tissue causing
damage by close contact with cells and matrix. During activation, azurophil
granule proteinases are expressed on the neutrophil membrane (148) and in
vitro, over 95% remain associated with the cell by a charge dependent
mechanism while
<
5% is released (149,150). Free NE may accumulate from
degranulating neutrophils or, in contrast with apoptotic cells, may be freely
released during cell necrosis (151). In addition, the process of phagocytosis
may cause the release of significant quantities of proteinases into the media
(''sloppy eating''), especially during ''frustrated phagocytosis,'' when cells
attempt ingestion of large particles (152). Free NE can also be released from
activated macrophages, which scavenge the proteinase from apoptotic neu-
trophils via endocytosis and release it during the first 24 hr of their own
inflammatory response (153). This is important, as while cell-associated pro-
teinases have partial resistance to native inhibitors such as
a
1
-AT (148), free
NE is more readily inactivated by both serum and tissue-based inhibitors
(154) if sufficient quantities of inhibitors are present.
The concentration of free NE released from the granule falls exponen-
tially from 5mM (155). In healthy subjects, the serum concentration of
