Biomedical Engineering Reference
In-Depth Information
the pathogenesis of COPD or may highlight that a combination of predis-
posing factors is required to develop the disease. This observation is clearly
worthy of further studies.
2.
Interleukin-1
b
The macrophage
=
monocyte is also the primary cellular source of IL-1
b
,
which, like TNF-
a
, binds to neutrophils and increases expression of adhesion
molecules without being directly chemotactic. IL-1
b
also stimulates expres-
sion of metalloproteinases (29). Again, like TNF, increased levels of IL-1
b
have been found in sputum of patients with stable COPD, which increase
further during exacerbations (30). Furthermore, IL-1
b
production is
enhanced by cells cultured from smokers with COPD following cigarette-
smoke exposure compared with controls (31). Enhanced production of IL-
1
b
in patients with COPD would lead to greater expression of neutrophil
adhesion molecules, thereby recruiting more neutrophils into the interstitium.
Recently, the role of IL-1
b
in the development of emphysema has been
studied comparing an IL-1
b
type 1 receptor knock-out mouse with double
TNF-
a
receptor deficient, combined IL-
b
and TNF-
a
receptor deficient,
and wild-type mice after intratracheal instillation of porcine pancreatic elas-
tase. In all cases emphysema was noted after 24 hr of instillation, but con-
tinued to progress for more than 10 days after clearance of the elastase.
After 21 days, the emphysema seemed less in all knock-out mice com-
pared with the wild strain. However, only the TNF-
a
receptor deficient and
combined IL-1
b
and TNF-
a
receptor deficient mice showed a significant
reduction in emphysema compared with the wild strain and also the single
knock-out animals. The authors suggest that 27% of total emphysema seen
could be related to the IL-1
b
type 1 receptor, 36% to TNF-
a
type 1 and 2
receptors, and 81% due to combination of the two receptor groups (18%
more than one would expect if the results are simply additive). Using their
mathematical model, only 20% of emphysema was due to the initial elastase
insult, whereas 80% was due to the subsequent inflammatory process (32).
This animal model suggests that both IL-1
b
and TNF-
a
are important in
the pathogenesis of COPD, but the exact relationship between these impor-
tant proteins is still unknown.
B. Chemoattractants
Neutrophils possess unique receptors for at least five chemotactic stimuli
including leukotriene B4 (LTB4), complement protein C5a, platelet-activat-
ing factor (PAF), bacterial peptides, including formyl-methionyl-leucyl-
phenylalanine (fMLP), and a variety of other chemokines.
1.
Leukotriene B4
Leukotriene B4 is mainly produced by monocytes, alveolar macrophages,
and activated neutrophils and is derived from cell membranes. Cytosolic
