Biomedical Engineering Reference
In-Depth Information
destroying the lung parenchyma. Neutrophils release a large array of serine
proteases including neutrophil elastase, proteinase 3, and cathepsin G, all of
which are able to induce emphysema in animal models (34). The release of
these serine proteases may be directly or indirectly encouraged by cigarette
smoking.
There is now increasing evidence that metalloproteinases (MMP)
derived from neutrophils and particularly from macrophages are likely to
contribute to lung injury. Indeed, macrophages are capable of producing
MMP-1 (collagenase), MMP-9 (gelatinase B), MMP-12 ( macrophage elas-
tase), and others (35). The activity of these MMPs may be counteracted by
tissue inhibitors of matrix metalloproteinases (TIMP) including TIMP-1,
TIMP-2, and TIMP-3 (19). Of interest, macrophages can also produce elas-
tolytic cysteine proteinases including cathepsin K, L, and S which may
damage the lung (19). As proposed by Shapiro (35), a disregulated expres-
sion of macrophage MMPs, induced either directly or indirectly by cigarette
smoking exposure, could lead to the lung destruction characteristic of
emphysema. The results of recent studies on chronic cigarette smoke expo-
sure in mice support this hypothesis. In fact, when MMP-12 knocked out
mice (MMP-12
=
) were exposed to chronic cigarette smoking, they failed
to develop emphysema and failed to recruit macrophages to the lung. In
contrast, the smoke-exposed wild type mice (MMP-12
þ
=
þ
) develop both
emphysema and macrophage recruitment (36). According to the authors,
these data suggest that cigarette smoking induces constitutive macrophages
to produce MMP-12, which in turn cleaves elastin, thus generating frag-
ments chemotactic for monocytes. This positive feedback would perpetuate
the accumulation of macrophages and lung tissue destruction (35). How-
ever, it has been recently shown that, in mice, smoke-induced tissue damage
requires not only macrophage metalloelastase, but also neutrophils (37), and
that TNF-
a
plays a central role in the process (38). All these observations
suggest that, in mice, MMP-12 mediates smoke-induced inflammation by
releasing TNF-
a
from macrophages, with subsequent endothelial activation,
neutrophil influx, and matrix damage caused by neutrophil-derived pro-
teases (39). As pointed out by Snider (40), in this model, macrophages
and TNF-
a
are essential to the process, but neutrophils and their proteases
are the final arbiters of matrix damage.
Whether neutrophil-mediated tissue destruction could explain smok-
ing-induced emphysema in humans as well is still controversial. Although
neutrophils have the potential to induce tissue damage, lung destruction is
not a significant feature of other pulmonary diseases where neutrophilia is
even more prominent, such as pneumonia, cystic fibrosis, bronchiectasis,
and adult respiratory distress syndrome (ARDS) (19). Therefore, this
mechanism may not fully explain the loss of lung tissue in cigarette smok-
ing-induced human emphysema. A possible alternative mechanism of lung
damage is a failure of the repair process. In vitro experiments have shown
