Biomedical Engineering Reference
In-Depth Information
chambers similar to those described in the past for other species, results in a
variety of changes in lung structure. The mouse upper airway differs from
humans in that submucosal glands are sparse and restricted to the trachea.
Similar to humans, mice have ciliated epithelial cells that are altered in
response to cigarette smoke. Epithelial cells lose their cilia and columnar
shape, and undergo metaplasia. Mice have less airway branching before
terminating in acinar units. Also, unlike humans, the mouse lower air-
space lacks respiratory bronchioles and the alveolar to airspace dimensions
are significantly less in the mouse than observed in other species including
rats. Overall, the mouse alveolar space is very similar to humans, and
following exposure to cigarette smoke, inflammatory cell recruitment and
airspace enlargement closely mimic the human response (22).
The main strength of mouse models is the ability to develop genetic
gain of function and loss of function models. Overexpression of proteinases
in transgenic mice was used by D'Armiento et al. (23) who found that a
human collagenase-l (MMP-1) transgene driven by the haptoglobin reporter
unexpectedly resulted in lung-specific expression in several independent
founder lines. These mice developed enlarged airspaces characteristic of
emphysema. This was the first demonstration that an MMP could directly
cause emphysema. Also, since MMP-1 is inactive against mature elastin, this
result suggested that collagen degradation was sufficient to cause emphy-
sema. This study raises the important concept that collagen turnover is
involved in emphysema. Clearly, there is clearly loss of collagen from
destroyed alveoli but there is also excess collagen accumulation in the small
airways (24). Thus, collagen turnover in emphysema is likely important but
complicated.
As discussed above, overexpression has limited ability to decipher dis-
ease pathogenesis in that it may tell us that a protein in excess can cause a
pathologic picture similar to a disease process, but does not prove that in the
context of a disease, this protein is responsible. Gene targeting or targeted
mutagenesis by homologous recombination in embryonic stem cells has
allowed investigators to generate strains of mice that lack individual pro-
teins, providing specific loss of function models. Combination of gene tar-
geting with the cigarette smoke exposure model provides an opportunity
to perform highly controlled experiments that differ with respect to expres-
sion of a single protein in mammals. Strains of mice deficient in individual
candidate proteinases can be compared to determine their contribution to
the development of emphysema in response to cigarette smoke. However,
if the protein is expressed during development, then one might confuse
developmental effects from acquired. In the case of airspace enlargement,
this is of particular concern.
Macrophage elastase (MMP-12), nearly undetectable in normal
macrophages, is expressed in human alveolar macrophages of cigarette smo-
kers and in patients with emphysema, but not normal lung tissue. Applica-
