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ALTERED GENE EXPRESSION AND AIRWAY REMODELING IN TWO CIGARETTE SMOKE MODELS OF COPD IN THE MOUSE
e60
Meeting abstracts
ALTERED GENE EXPRESSION AND AIRWAY REMODELING IN TWO CIGARETTE SMOKE MODELS OF COPD IN THE MOUSE K. Norton, M. Freke, S. Groom, S. Mason Charles River Preclinical Services, Montreal, Quebec, Canada The purpose of this study was to develop a model that adequately replicates the physiological and molecular characteristics of COPD and that could be used to evaluate the efficacy of new chemical entities to delay its onset. Changes in gene expression and lung remodeling were evaluated in two alternative smoke models. C57BL/5 mice, known to be resistant to smoke, were exposed to an 11% air stream of 2R4F low nicotine research cigarettes for 5 h daily, over a 1-week period, by whole body inhalation. Smoke sensitive A/J mice were exposed to vehicle, 4% smoke, 4% smoke + LPS (known for inducing neutrophilia) or 4% smoke + rolipram (a PDE4 inhibitor shown to decrease the influx of inflammatory cells to the site of inflammation) for 2 h daily, over a 3 month period. No changes in lung pathology or gene expression were noted in the C57BL/5 mice. A/J mice (both smoke and smoke-LPS treated), displayed chronic pulmonary inflammation, characterized by accumulation of macrophages and CD4+, CD8+ and CD19+ T cells. In addition, increased expression of TNFα, INFγ, IL10, IL18, KC (Gro-α/CXCL1), Seperine2 and Rtp801 and changes in lung morphology including goblet cell metaplasia, airway wall thinking and alveolar enlargement were observed. Treatment with rolipram in smoke challenged A/J mice resulted in decreased cellular infiltrate and airway remodeling compared to smoke and smoke-LPS challenge animals. Exposure of A/J mice to smoke provides a suitable model for characterizing COPD and can be used to test effect of novel compounds to delay the progression of the disease. doi:10.1016/j.vascn.2007.02.120
TECHNIQUES TO ENABLE PERFORMANCE OF A SINGLE STUDY IN NON-RODENTS TO MEET ICH S7A CORE BATTERY REQUIREMENTS S. Mason, H. Penton, K. Norton Charles River Preclinical Services, Montreal, Quebec, Canada ICH S7A core battery requirements mandate assessment of effects on the CNS, respiratory and cardiovascular systems prior to first dosing in man. In general, separate studies are performed due to data collection procedures impacting on data quantity and quality for certain endpoints. Recent advances however have now made possible the performance of a single study in dogs or monkeys to cover all three areas in the same animals. For cardiovascular assessment, animals can be instrumented with standard telemetry devices such as a DSI D70-PCT to provide data on blood pressure and the ECG. CNS evaluations can also be carried out in the same animals through use of a modified functional observational battery (FOB) and careful timing of this assessment can have minimal impact on cardiovascular data quality. Respiratory data collection in non-rodents has traditionally been a difficult procedure due to stress from restraint causing much variation. To address this issue, our Laboratory has validated the VivoMetrics Lifeshirt® in dogs and monkeys for continuous non-invasive collection of respiratory data. Both cardiovascular and respiratory data can be collected using the DSI Gould Ponemah system in real-time, and can be further analyzed post-acquisition as required. The incorporation of the LifeShirt® system into routine monitoring for respiratory effects in studies of this type has potential to reduce the number of animals used in safety assessment, and additionally provides both cost and time benefits for drug development. doi:10.1016/j.vascn.2007.02.121
Meeting abstracts
ALTERED GENE EXPRESSION AND AIRWAY REMODELING IN TWO CIGARETTE SMOKE MODELS OF COPD IN THE MOUSE K. Norton, M. Freke, S. Groom, S. Mason Charles River Preclinical Services, Montreal, Quebec, Canada The purpose of this study was to develop a model that adequately replicates the physiological and molecular characteristics of COPD and that could be used to evaluate the efficacy of new chemical entities to delay its onset. Changes in gene expression and lung remodeling were evaluated in two alternative smoke models. C57BL/5 mice, known to be resistant to smoke, were exposed to an 11% air stream of 2R4F low nicotine research cigarettes for 5 h daily, over a 1-week period, by whole body inhalation. Smoke sensitive A/J mice were exposed to vehicle, 4% smoke, 4% smoke + LPS (known for inducing neutrophilia) or 4% smoke + rolipram (a PDE4 inhibitor shown to decrease the influx of inflammatory cells to the site of inflammation) for 2 h daily, over a 3 month period. No changes in lung pathology or gene expression were noted in the C57BL/5 mice. A/J mice (both smoke and smoke-LPS treated), displayed chronic pulmonary inflammation, characterized by accumulation of macrophages and CD4+, CD8+ and CD19+ T cells. In addition, increased expression of TNFα, INFγ, IL10, IL18, KC (Gro-α/CXCL1), Seperine2 and Rtp801 and changes in lung morphology including goblet cell metaplasia, airway wall thinking and alveolar enlargement were observed. Treatment with rolipram in smoke challenged A/J mice resulted in decreased cellular infiltrate and airway remodeling compared to smoke and smoke-LPS challenge animals. Exposure of A/J mice to smoke provides a suitable model for characterizing COPD and can be used to test effect of novel compounds to delay the progression of the disease. doi:10.1016/j.vascn.2007.02.120
TECHNIQUES TO ENABLE PERFORMANCE OF A SINGLE STUDY IN NON-RODENTS TO MEET ICH S7A CORE BATTERY REQUIREMENTS S. Mason, H. Penton, K. Norton Charles River Preclinical Services, Montreal, Quebec, Canada ICH S7A core battery requirements mandate assessment of effects on the CNS, respiratory and cardiovascular systems prior to first dosing in man. In general, separate studies are performed due to data collection procedures impacting on data quantity and quality for certain endpoints. Recent advances however have now made possible the performance of a single study in dogs or monkeys to cover all three areas in the same animals. For cardiovascular assessment, animals can be instrumented with standard telemetry devices such as a DSI D70-PCT to provide data on blood pressure and the ECG. CNS evaluations can also be carried out in the same animals through use of a modified functional observational battery (FOB) and careful timing of this assessment can have minimal impact on cardiovascular data quality. Respiratory data collection in non-rodents has traditionally been a difficult procedure due to stress from restraint causing much variation. To address this issue, our Laboratory has validated the VivoMetrics Lifeshirt® in dogs and monkeys for continuous non-invasive collection of respiratory data. Both cardiovascular and respiratory data can be collected using the DSI Gould Ponemah system in real-time, and can be further analyzed post-acquisition as required. The incorporation of the LifeShirt® system into routine monitoring for respiratory effects in studies of this type has potential to reduce the number of animals used in safety assessment, and additionally provides both cost and time benefits for drug development. doi:10.1016/j.vascn.2007.02.121