Biomedical Engineering Reference
In-Depth Information
Figure 3
Inflammatory mechanisms in COPD. Cigarette smoke (and other irri-
tants) activates macrophages in the respiratory tract that release neutrophil chemo-
tactic factors, including interleukin-8 (IL-8) and leukotriene B
4
(LTB
4
). These cells
then release proteases that break down connective tissue in the lung parenchyma,
resulting in emphysema, and also stimulate mucus hypersecretion. These enzymes
are normally counteracted by protease inhibitors, including
a
1
-antitrypsin, secretory
leukoprotease inhibitor (SLPI) and tissue inhibitor of matrix metalloproteinases
(TIMP). Cytotoxic T cells (CD8
รพ
) may also be recruited and may be involved in
alveolar wall destruction. Fibroblasts may be activated by growth factors releases
from macrophages and epithelial cells.
such as destruction of connective tissue (emphysema) and fibrosis (obstruc-
tive bronchiolitis). What is not yet understood is how these mechanisms
change with time and the sequence of events.
IV. WHAT ARE THE AMPLIFYING MECHANISMS
?
The inflammatory changes and protease imbalance in COPD are also seen in
cigarette smokers without COPD, but to a lesser extent (17,52,60-62), sug-
gesting that the accelerated decline in lung function in COPD may be due to
amplification of the normal pulmonary inflammatory response to irritants
(Fig. 4). This may be due to increased production of inflammatory media-
tors and enzymes, or because of defective endogenous anti-inflammatory
or antiprotease mechanisms. These differences might be explained by poly-
morphisms in the genes encoding cytokines, proteases, anti-inflammatory
proteins, and antiproteases (63,64).
Another hypothesis is that these differences are due to latent virus
infection (65). The latent adenovirus sequence E1A is more commonly
detected in the lungs of patients with emphysema than in matched smoking
control subjects and is correlated with an increased inflammatory response
