Chest
Volume 122, Issue 6, Supplement, December 2002, Pages 301S-306S
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Animal Models of Cigarette Smoke-Induced COPD*

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Objectives

To review the animal models of COPD, and to compare these data to those found in humans.

Results

Smoke-induced animal models can produce emphysema, although the lesions are not generally close mimics of human emphysema, as well as increases in mucous-secreting cells and vascular changes including pulmonary hypertension. There is considerable species-to-species variation in the degree and/or presence of these different abnormalities, so that care has to be used in selecting a species to study. Remarkably little information is available about the biochemical and molecular changes induced by cigarette smoke in animal models.

Conclusions

Great insights into the pathology of chronic obstructive lung disease have been made using various animal models.

Section snippets

Emphysema Types

There is much literature detailing the descriptions of emphysematous lung destruction in cigarette smokers.1 In general, the majority of the emphysema produced by smoke is of the centriacinar type, although panacinar emphysema may occur in conjunction with centriacinar emphysema.

There is also no doubt that chronic exposure of animals to cigarette smoke will produce emphysema, as defined by the National Heart, Lung, and Blood Institute.2 The length of time required to produce emphysema varies

Epithelial Cell Alterations

Goblet cell metaplasia is a frequent finding in the large and small airways of cigarette smokers,2627 but it has been difficult to find consistent results, probably due to sampling difficulties because the metaplastic cells are not randomly distributed, but occur in clusters. Metaplasia is also a frequent feature in asthmatic large and small airways.

In animals, secretory cell metaplasia as a response to cigarette smoke appears to be of greater intensity than that found in humans. Workers have

Airway Wall Alterations

In humans, the structure of the larger airways has been examined, with evidence of muscle thickening, particularly in those subjects with airflow obstruction, although there was a wide degree of variation in any group examined and there may also be variation from site to site.32 In examining biopsy specimens from the larger airways of cigarette smokers, it appears that when both chronic bronchitis and airflow obstruction exists, there are increases in the overall T-cell population,3334 with

Alterations of the Pulmonary Vasculature

In humans, 6% of subjects with COPD will acquire pulmonary hypertension and, ultimately, cor pulmonale. Morphometric examination of the pulmonary vascular tree has demonstrated intimal and medial thickening of the muscular arteries, and muscularization of the small arteries/arterioles, which appeared to have a progressive increase in severity from nonsmokers to smokers without COPD to smokers with COPD.41

To our knowledge, the only model in which the vasculature has been examined is the guinea

Alterations of Cytokines

The cytokine profile in smokers has recently become of great interest to investigators, largely because of the differentiation of the cytokine secretion profiles by the subset of CD4 lymphocytes that become activated. These subsets have been termed T-helper (Th)-1 and Th-2, and each has its characteristic cytokine secretion pattern.45 When bronchial biopsy samples were obtained in current and ex-smokers with chronic bronchitis, and compared with data from nonsmokers, there were increased

Evidence of Cell Proliferation or Induction of Apoptosis

There are few data in humans in regards to the balance between cell proliferation and cellular apoptosis in cigarette smokers. Kasahara et al51 demonstrated an increase in apoptotic cells in the lungs of smokers with emphysema, while there was no difference between the numbers of cells in nonemphysematous smokers and nonsmokers. Interestingly, however, Yasuda and colleagues52 measured plasma sFas, which is an inhibitor of apoptosis and found an increase in those subjects with severe COPD.

In

Systemic Effects

Human smokers, particularly those with COPD, often have significant weight loss, and those patients who lose larger amounts of weight appear to have a greater mortality than those with stable weight.55 Almost all of the models that have evaluated this parameter have demonstrated a failure of smoke-exposed animals to gain weight.692940 We know of no study that has been constructed to determine whether the animals actually lose weight. In our guinea pig model, the smoke-exposed animals weighed

Conclusion

This article has reviewed data from a wide variety of animal models of cigarette smoke-induced lung disease, and compared these results to the information available from human smokers. There is a basic degree of similarity among the studies, although certainly they differ in the degree of abnormalities produced, and the length of exposure time and protocols used to induce the lesions. The lesions of the lung parenchyma are not an absolute mimic of human emphysema, except perhaps in the dog

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    Supported by grants from the Heart and Stroke Foundation of British Columbia and Yukon, Canadian Institutes of Health Research, and the British Columbia Lung Association.

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