Hyperpolarized 3He atoms entering lung acini diffuse. Acinar airways covered with alveolar sleeves serve as obstacles to the path of diffusing 3He atoms; hence diffusivity of 3He gas can provide information on the acinar airways geometry. Specific Aim 1 To develop a new technique based on 3He diffusion MRI for tomographic -ung biopsy- This technique will allow in vivo non-invasive quantitative assessment of lung microstructural parameters at the alveolar level and serve as a powerful tool for identifying emphysema. We will extend our existing mathematical model that is based on a realistic structure of lung and relates anisotropic 3He ADC measurements in lung to lung microstructural parameters at the alveolar level. We will test this model on healthy mice and canines with different levels of emphysema. The mice will be used for sophisticated multi-dimensional MR experiments that would not be possible or safe with humans. The canine model, expressing a controlled level of emphysema, has physiology similar to human and will be used (a) to establish a set of essential parameters characterizing lung microstructure that can be obtained from 3He diffusion MRI and (b) to find optimal values for 3He diffusion-sensitive MRI pulse sequence parameters for use in humans. The current imaging standard for in-vivo evaluation of emphysema - CT - quantifies the density of lung tissue but does not provide information on lung tissue microstructure and can not readily distinguish between ventilated and non-ventilated lung regions. 3He MRI is capable of providing information on both lung ventilation and microstructure. Specific Aim 2 To establish a quantitative set of relationships between regional lung ventilation as determined by 3He spin-density MRI, lung microstructural parameters as determined by 3He diffusion MRI, and X-ray linear attenuation coefficient (LAC) obtained from CT images. These relationships will provide new insightful clinical information that can be inferred from CT images. We expect correlation between these measurements (ventilation, ADCs and CT) because abnormal, permanent enlargement of acinar air-spaces, accompanied by destruction of their walls with emphysema progression results in (a) decreased lung tissue density and increased 3He diffusivity (lesser restrictions to diffusion); and (b) reduction and eventual loss of elastic lung tissue recoil and loss of lung ventilatory function. We will conduct all studies on a canine model expressing a controlled level of emphysema and human subjects with different levels of emphysema. A quantitative relationship between 3He MRI data and LAC obtained from CT will be found through image segmentation procedure based on multi-modality registration of CT data with 3He MRI data. Overall, we propose to develop further, verify on animal models, apply to patients with emphysema and test against current imaging techniques new 3He MRI methods for imaging of human lung. These methods take advantage of the MR imaging properties of hyperpolarized 3He gas and will allow quantitative evaluation of lung ventilatory function as well as lung microstructure at the alveolar level. A comprehensive clinical picture of emphysema progression, from initial onset of the alveolar deformation to the final stage, characterized by dramatic loss of lung function, will be established. New methods will be sensitive enough to allow early diagnosis of emphysema that will improve patient treatment. Our methods will also allow for more accurate selection of patients suitable for LVRS that might substantially improve the outcome of LVRS