While Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the US and affects 30 million Americans, high-resolution non-invasive image-based assessment of lung health is lagging behind imaging of the other vital organs. The availability of a low-cost, highly quantitative modality for 3-D imaging of lung function would improve early diagnosis and discrimination of diseases, accelerate testing of therapies by pharmaceutical companies, and ultimately assist in more personalized disease management and intervention in clinics and hospitals. Hyperpolarized gases can address this need. 3He has enjoyed the most widespread study largely due to the availability of mature polarization technologies. Recently high polarization of 129Xe in liter quantities has become available due to innovations by the UNH group, allowing the potential scientific advantages of hyperpolarized 129Xe imaging to be investigated. Depolarization of hyperpolarized atoms, both 3He and 129Xe, in lungs is dominated by the presence of paramagnetic oxygen gas molecules. T1 decay constant protocols using hyperpolarized 3He have mapped local oxygen partial pressures and furthermore show sensitivity to oxygen uptake by the bloodstream within a breath hold. Hyperpolarized 129Xe has the same sensitivity to oxygen and much lower diffusion, in addition to practical advantages of low cost and abundant supply. We propose to demonstrate that 129Xe can compete successfully with 3He by performing the following measurements:1. We will perform signal loss contrast imaging with mixtures of hyperpolarized 129Xe and oxygen in phantoms. 2. We will perform signal loss contrast imaging using hyperpolarized 129Xe and oxygen in human subjects. 3. We will compare signal loss during a breath hold with other hyperpolarized xenon metrics of lung health to quantify uncertainties. Back to back measurements with published and new pulse sequences will reveal comparative merits of each. Multiple measurements in the same subject, both during the same imaging session and after repositioning will provide a measure of the systematic errors, including those resulting from partial volume effects in voxels. We will explore reducing partial volume effects using proton imaging. Comparing measurements after breath holding with others after hyperventilating will allow separation of xenon lost to the bloodstream and signal lost due to O2. The US FDA has approved our hyperpolarized xenon for Phase 2 trials in subjects with mild to moderate lung disease.While both 129Xe and 3He can be used to measure local alveolar oxygen concentration and determine the uptake of oxygen by the lungs, each poses challenges to quantitative interpretation. We propose to push the quantitative limits to extracting lung functional health from 129Xe measurements using a variety of methods, in order to develop a diagnostic protocol suite that could help Americans suffering from Chronic Obstructive Pulmonary Disease (COPD). Of the two gases being investigated for hyperpolarized gas MRI, 129Xe offers the best possibility of widespread acceptance and commercialization due to its low cost and inexhaustible supply. [unreadable] [unreadable] [unreadable]