Hyperpolarized ¹²⁹Xe enables direct imaging of pulmonary function by exploiting its combination of tissue solubility and abundant chemical shifts. These properties have been particularly promising for more sensitive monitoring of idiopathic pulmonary fibrosis (IPF) ¹. In these patients, the ratio of ¹²⁹Xe uptake in red blood cells (RBC) to barrier tissues is dramatically reduced ². Moreover, combining interleaved excitation of gas- and dissolved-phases with a Dixon-based decomposition has enabled imaging of the ¹²⁹Xe distribution in the gas, barrier tissue, and RBC compartments in a single breath ³. These images demonstrate regional differences in RBC:Barrier ratios. However, to date it is not clear whether these alterations are caused by decreased ¹²⁹Xe uptake in RBCs, increased ¹²⁹Xe uptake in barrier, or a combination of both. We therefore sought to test whether the gas-phase source distribution could serve as a reference to separately evaluate regional changes in barrier and RBC in IPF.The study enrolled 5 normal subjects (Age = 35±10) and 7 IPF patients (Age = 65±5), who underwent single-breath gas and dissolved-phase ¹²⁹Xe MRI after inhaling 0.75 L HP ¹²⁹Xe polarized to 16-18%. Imaging used an interleaved 3D radial sequence at 1.5 T (GE EXCITE 15M4) with flip-angles = 1.5/22º, TR/TE = 8/0.9 ms, FOV = 40 cm. Images were reconstructed as recently described ⁴, onto a matrix, and separated into RBC and barrier components ³. The RBC and barrier images were then divided on a pixel-by-pixel basis by the gas-phase image to generate RBC:Gas and Barrier:Gas ratio maps. In order to scale these maps so that they could be compared across patients, a linear normalization was applied using the assumption that the highest RBC:Gas values in each patient represent regions of maximal gas exchange, and are therefore equivalent. This enabled a scaling factor to be determined such that the top percentile of RBC:Gas intensities were unity. This same scaling factor was then applied to the Barrier:Gas maps. The figure shows normalized ratio maps and histograms from a normal subject, a patient with early-stage IPF at baseline and 5-month follow-up. In the IPF patient at baseline, Barrier:Gas is 84% higher than in the control, and at 5-month follow-up, it increases to be 100% higher. Similarly, the RBC:Gas is regionally diminished in the IPF patient compared to the control. At 5-month follow-up some regions are diminished even further, particularly at the base of the lungs. These findings were confirmed in the larger population as depicted in the graph. In general most IPF subjects exhibit a mean RBC:Gas ratio that is close to that in normal subjects. It appears to be primarily the barrier that is greatly increased in IPF until the patient reaches a very severe stage and RBC:Gas begins to diminish.IPF appears to be characterized primarily by an increased barrier intensity, which is what dominates the observed reduction of RBC:Barrier. By contrast it appears that RBC:Gas remains relatively normal until very late in the disease progression. This may aid in the interpretation of disease burden and provide a better way to detect disease progression. Ultimately, Barrier:Gas maps may provide the most sensitive means to evaluate therapeutic response.