Biomedical Engineering Reference
In-Depth Information
B. Animal Models
1.
Elastase and Chemical-Induced Emphysema
Since Gross' initial experiments, investigators have instilled a variety of pro-
teinases into the lungs of many small and large animals. A common feature
is that administration of elastolytic enzymes including pancreatic elastase,
neutrophil elastase, and proteinase 3 results in airspace enlargement
(3,17-19). Pancreatic elastase produces consistent and impressive airspace
enlargement. Instillation of non-elastolytic enzymes such as bacterial
collagenase do not cause emphysema. Overexpression of proteinases, either
by simple intratracheal instillation or more modern transgenic methods, can
determine whether an enzyme has the capacity to cause emphysema (when
applied to mature, fully developed lungs). However, these models cannot
identify which proteinases are involved in the pathogenesis of emphysema
associated with cigarette smoking, nor can they be used to decipher events
upstream of proteinase release. Moreover, cigarette smoke exposure may
cause a variety of other abnormalities not observed with simple overexpres-
sion of a proteinase. Nevertheless, the elastase model continues to have uti-
lity due to its relative simplicity and the fact that it allows for first order
approximation for study of downstream events particularly alveolar repair.
For example, elastase instillation has recently been used to demonstrate that
retinoic acid has the capacity to promote alveolarization and lung repair in
adult male rats (20). In addition, although instillation of elastase causes
immediate airspace enlargement, there is an ensuing inflammatory response
and further lung destruction from endogenous proteinases. Whether chemo-
tactic mechanisms and participating proteinases are similar to COPD is
unclear but of interest.
2. Cigarette Smoke-Induced Emphysema
A variety of chemicals and irritants have been used in experimental animals
to induce inflammation and emphysema including LPS, cadmium chloride,
nitrogen dioxide, inorganic dusts, and ozone. Results from these models
have been reviewed elsewhere (21). These models have contributed to our
knowledge of lung injury, but none have replicated exposure to cigarette
smoke as a model for authentic COPD.
Several animal species have been exposed to cigarette smoke over the
years including dogs, rabbits, guinea pigs, and rodents (21). Recent focus
has been on the mouse since it provides unique opportunities for genetic
manipulation. Other advantages of the mouse include extensive knowledge
of mouse biology, abundant mouse cDNA probes and antibodies, rapid
breeding, large litter sizes, small size (advantage for dosing expensive phar-
maceutical agents, a disadvantage for surgical models), and relatively cheap
housing. Exposure of mice to long-term cigarette smoke, using smoking
