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The Guinea Pig as a Model for Tobacco Smoke – Induced COPD Reference: A Model of Tobacco Smoke-Induced Airflow Obstruction in the Guinea Pig. Joanne L. Wright and Andrew Churg. CHEST 2002: 121:188S-191S. This review of the guinea pig as a model of cigarette smoke (CS) induced - chronic obstructive pulmonary disease (COPD) was presented in recent medical symposium on COPD. Guinea pigs have long been used as models for the study of asthma. In 1974 a method of administering CS to guinea pigs was first published. The first studies concentrated on vascular permeability and the related migration of neutrophils through tracheal epithelium after exposure to CS. Later the repair phase of this morphological damage was described using horseradish peroxidase and electron microscopy. Secretory cell metaplasia in guinea pig airways observed after CS is assumed due to chronic irritation similar to goblet cell metaplasia observed in human smokers’ bronchioles. The increased responsiveness of the airway described is thought to be caused by CS inactivation of the protective airway neutral endopeptidase. More detailed experiments have now been performed using guinea pigs as models of CS-induced COPD. Dr. Wright’s laboratory (Department of Pathology, University of British Columbia, Vancouver, BC) studies both acute and chronic responses to cigarette smoke in the guinea pig respiratory tract. The parenchymal region of the lung is most frequently studied for change and COPD after CS exposure. Morphology yields information on physical destruction of the alveolar region. When respiratory mechanics are studied in addition to morphology, correlations can be made between CS smoke-induced structural and functional changes. Pulmonary airflow obstruction with air trapping occurs within 10 minutes of exposure to CS smoke. Simultaneously excess neutrophils appear in peripheral blood and in broncho-alveolar lavage (BAL) fluid. The classic airspace enlargement of emphysema appears after 3 m of CS exposure. Gas trapping, increased total lung volume and shifts in the pressure-volume and flow-volume curves are also observed. These changes cease at the end of the CS smoke exposure although they do not reverse. Surprisingly pores of Kohn do not change in size. However new and larger holes are found that connect the alveoli resulting in disrupted airflow. The role of proteases in CS-induced emphysema in the guinea pig has also been studied. CS exposure leads to collagenolytic activity. Another investigating group reported increased protease levels originating from inflammatory cells in the lung within 4 weeks of exposure to 20 cigarettes/day. This group found decreased collagen followed by increased collagen 3 m later at the exposure level of 5 cigarettes/day. It is assumed that emphysema involves the pulmonary vasculature because chronic smokers develop pulmonary hypertension. Guinea pigs also develop hypertension although it is not from the destruction of the capillary bed as was expected. Instead there is an increase in cell proliferation in the muscular vessels leading to an increase in the percent of muscularized small arteries. CS is also thought to change the tone of muscles in addition to changing the structure. More investigation of the mechanism of CS induced pulmonary hypertension should yield helpful information. The authors discuss this guinea pig model of CS-induced COPD relative to models using both rats and mice. Various studies in rats with different CS dosing regimens show:
Mice are new to the use of the CS model. However they are becoming popular because of the availability of transgenically modified or knock-out strains. In addition some strains normally develop emphysema as they age. Inflammation of airways, within the alveoli and increases in airspace size including both the size of alveolar ducts and spaces have been documented after long exposures to CS in mice. The authors summarize the advantages of using the guinea pig to study the effect of (CS) on the respiratory tract. Guinea pigs exhibit similar morphologic and physiologic changes as are found in human smokers in response to similar doses of CS when dose is measured by carboxyhemoglobin levels. Increased pulmonary arterial pressure may be observed in some guinea pigs after CS exposure. In contrast rats do not show physiological changes in the vascular system after CS even when cell proliferation can be seen in these vessels. Problems with the guinea pig model are primarily technical at this point. Although they are gentle and easy to handle, guinea pigs are more difficult to intubate than are rats. Thus ventilation and pulmonary function measurements are more difficult to perform than in rats and require technical expertise. A high level of endogenous ribonulcease requires care when handling tissue for accurate measurements RNA. Although fewer gene sequences are known for the guinea pig than for the rat or mouse resulting in less known protein sequences, this should change in the future with advances in gene sequencing. There is also a crossover to human genes from guinea pig genes allowing human antibodies, ELISA and Western blot tests to be used. Editorial Comment: This review concentrates on studies of the guinea pig response to CS. It also addresses CS exposure models of rats and mice. Studies of the effects of cigarette smoke on the lungs of animals undoubtedly show a variety of results based not only on the species studied, but the dose of smoke administered and the type of cigarette used to provide the smoke. Unfortunately detailed information on the smoke exposure itself is not always available as it was with simple gas exposures such as those to ozone and NO2. As the study of the effects of cigarette smoke on the lung advances, there will surely be more standard procedures used. Thus it will be possible to compare the results of different studies involving different species and gain more accurate information of the effect and mechanism of action of cigarette smoke on the respiratory tract.
By: Susan G. Shami, ScD Science Editor
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