Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is the only major cause of death for which the age-adjusted death rate has increased in recent years. As progress is made in understanding the genetic and molecular pathways involved in COPD, there is a growing need for improved tools to characterize lung function for applications such as coupling genetic subtypes to phenotype expression, monitoring functional response to new treatments, or aiding in the rapid development of novel respiratory drugs. Nonetheless, despite a myriad of technical advances in medical imaging, it remains challenging to obtain in-vivo regional depiction and quantification of the most basic physiological functions of the lung - gas delivery to the airspaces and gas uptake by the lung parenchyma and blood - in a manner suitable for routine application in humans. To address this unmet need, this project takes advantage of a method recently developed by our group, based on magnetic resonance imaging (MRI) of hyperpolarized xenon-129 (hypXe129), that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation, from a single short breath-hold acquisition suitable for subjects with compromised respiratory function. The first aim of this project is to implement, and validate in human subjects, key improvements to this technique, including the ability to separately depict in the images the fraction of hypXe129 dissolved in red blood cells and that dissolved in lung parenchyma/plasma. The second aim is to characterize gas uptake in the healthy lung, as reflected by dissolved-hypXe129 signals, by measuring signal behaviors as a function of measurement parameters and lung inflation in healthy subjects, and then derive optimized protocols, based on the signal-behavior data, for measuring the associated 3D distributions of gas uptake. These optimized protocols will be validated in subjects with mild and severe COPD. The third and final aim is to perform an exploratory study in 20 healthy control subjects, 10 smokers with normal spirometry and 30 subjects with COPD, ranging from GOLD stage 1 to 3, to characterize, as a function of disease severity, the normalized gas- uptake distributions for dissolved hypXe129 and for the fractions of hypXe129 dissolved in red blood cells and lung parenchyma/plasma. These gas-uptake results will be compared to results from standard computed tomography (CT) of the chest and pulmonary function testing. Successful completion of the proposed project will result in an improved, optimized version of the method for simultaneous MR imaging of ventilation and gas uptake that provides normalized regional gas-uptake values, which can be quantitatively compared among subjects. This technique offers important functional information about the lung, which is not available from any existing clinical imaging modality, and has substantial potential to provide unique, physiologically relevant, and clinically important information about COPD.