Chronic obstructive pulmonary disease is projected to become the 3rd leading cause of death worldwide by 2030. Currently, 200 million people worldwide have been diagnosed with COPD, and many more are living with undiagnosed disease. COPD has no cure and no drugs that lead to improvements in long-term survival. Drug discovery is challenging due to a poor understanding of COPD pathogenesis. To study COPD, rodent models have been developed, with daily exposures to tobacco cigarette smoke over a 6-month period inducing symptoms. Measurements are typically done on histological slides, assessing airway wall thickening and markers of emphysema. These post-mortem techniques are unable to assess how the disease is progressing or how these observed structural changes impact lung function. To identify changes in lung structure and function in a smoking exposure model, we used respiratory-gated micro-computed tomography (micro-CT) and image-based measurements of lung structure and function. Micro-CT imaging was performed in anesthetized, free-breathing mice at baseline. The mice were then subjected to 6-months of exposure to tobacco cigarettes or ambient air, and rescanned. We also performed post-mortem lung compliance tests on 3-month smoke-exposed and age-matched control mice. Significant differences between smoke-exposed and control mice were observed for lung volume and functional residual capacity, which correlate well with the results of the lung compliance testing. In vivo respiratory-gated micro-CT in free-breathing animals is sensitive to changes in lung structure and function resulting from exposure to tobacco cigarette smoke, and is an effective tool to monitor the development of COPD in rodent models.
Chronic obstructive pulmonary disease (COPD) affects 200 million people worldwide, and is projected by the World Health Organization to be the third leading cause of death world-wide by 2030. Few drugs are available to treat COPD, and none that lead to improvements in long-term survival. A major problem for drug discovery is a poor understanding of COPD pathogenesis. Animal models of COPD rely on demonstration of emphysema and airway wall thickening on histology, which generally require 6 months of daily cigarette smoke exposure. Functional changes however may develop sooner as the disease process begins in small airways. To identify changes in lung micro-structure and function during daily cigarette smoke exposures (1 or 3 months), we used respiratory-gated micro-computed tomography (micro-CT) and image-based measurements of lung and airway volume and gas content. Mice were imaged pre-exposure, exposed daily to tobacco cigarette smoke, and imaged again. Images representing peak inspiration and end expiration were reconstructed with 0.075 mm isotropic voxel spacing. Significant differences were observed between pre-exposure and post-exposure scans for the lung volume, and air content at peak inspiration and for tidal volume in the control mice. These results suggest that the lung capacity of the mice continued to develop over the exposure period in control mice. The 3-month smoke-exposed mice exhibited increased lung volumes compared to 1-month and control groups for both respiratory phases. In vivo respiratory-gated micro-CT imaging is an effective non-invasive means of monitoring the progression of respiratory disease as early as 1 month into a smoke-exposure study.