PurposeChronic obstructive pulmonary disease (COPD) is an irreversible lung disease characterized by small-airway obstruction and alveolar-airspace destruction. Hyperpolarized Xe-129 diffusion MRI of lung is a promising biomarker for assessing airspace enlargement, but has yet to be validated by direct comparison to lung histology. Here we have compared diffusion measurements of hyperpolarized (HP) Xe-129 in explanted lungs to regionally matched morphological measures of airspace size. MethodsExplanted lungs from five COPD patients and two idiopathic pulmonary fibrosis (IPF) patients were imaged using MRI with hyperpolarized Xe-129 using a two-b-value gradient-echo diffusion sequence, and 34 histological samples were taken from these lungs for quantitative histology. Mean-linear-intercept (L-m) was compared with spatially matched measures of apparent diffusion coefficient (ADC) from Xe-129 MRI. ResultsThe mean ADC from COPD lung samples was 0.0710.011cm(2)/s, and for IPF lungs was 0.033 +/- 0.001cm(2)/s (P<10(-15) between groups). The mean L-m in COPD samples was 0.076 +/- 0.027cm and 0.041 +/- 0.004cm in IPF (P=2.7x10(-7) between groups). The Pearson-correlation between ADC and L-m measurements was r=0.59. ConclusionsDiffusion MRI of HP Xe-129 quantifies regional airspace enlargement in COPD. Xe-129 ADC showed much less overlap between groups than quantitative histology, consistent with our past experience with He-3 diffusion MRI in COPD. Magn Reson Med 77:265-272, 2017. (c) 2016 Wiley Periodicals, Inc.