The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized (3)He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii-parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials.

This report describes the measurement of water preexchange lifetimes and intra/extracellular content in intact, functioning mammalian brain. Intra-and extracellular water magnetic resonance (MR) signals from rat brain in vivo were quantitatively resolved in the longitudinal relaxation domain following administration of an MR relaxation agent into the extracellular space. The estimated intracellular water content fraction was 81% ؎ 8%, and the intra-to extracellular exchange rate constant was 1. 81 Knowledge of the rate constants governing exchange or, equivalently, the preexchange lifetime (or residence time) of water in the intra-and extracellular compartments of the mammalian brain would be extremely valuable for interpreting a wide range of magnetic resonance (MR) experiments. When compartment-sensitive MR measurements of water properties are made, the proper interpretation of experimental results requires a clear understanding of the governing exchange regime. This exchange regime is a function of the time scale of the experiment and the residence lifetimes of the molecule of interest in the relevant compartments. If the experimental time scale is long relative to the residence lifetime, the system is in fast exchange and observations reflect a dynamic averaging of compartment properties. If the experimental time scale is short relative to the residence lifetime, the system is in slow exchange and compartmental signals can be analyzed separately. For instance, considerable controversy currently exists as to the mechanism(s) underlying the change in water apparent diffusion coefficients (ADCs), which provide remarkable contrast in diffusion-weighted brain imaging (1). To better understand this contrast, it would be very useful to make intra-and extracellular compartmentspecific measurements of water diffusion. However, it is not possible to obtain such measurements unless the water exchange regime (fast, slow, or intermediate) relevant to the study is understood.In order to measure this exchange, one must discriminate between MR signals arising from water in the intra/ extracellular compartments. Were such discrimination possible, it would open the way for measurement not only of water preexchange lifetime and membrane permeability, but also the relative water content fractions of the two compartments. The relative water content fraction is believed to change under conditions of cell swelling and/or shrinkage, such as occurs with cell injury. In the study described below, we estimated the intra/extracellular water content ratios, water exchange rate constants, and membrane water permeability in intact mammalian brain.In theory, there are at least three ways to discriminate MR signal arising from different tissue compartments. One is based on chemical shift or resonance frequency. However, the 1 H resonance of water does not have a discernible resonance frequency difference between the intra-or extracellular spaces. In principle, it is possible to administer a chemical shift reagent to one compartment, shift...

Purpose:To quantitatively characterize early emphysematous changes in the lung microstructure of current and former smokers with noninvasive helium 3 ( 3 He) lung morphometry and to compare these results with the clinical standards, pulmonary function testing (PFT) and low-dose computed tomography (CT). Materials and Methods:This study was approved by the local institutional review board, and all subjects provided informed consent. Thirty current and former smokers, each with a minimum 30-packyear smoking history and mild or no abnormalities at PFT, underwent 3He lung morphometry. This technique is based on diffusion MR imaging with hyperpolarized 3 He gas and yields quantitative localized in vivo measurements of acinar airway geometric parameters, such as airway radii, alveolar depth, and number of alveoli per unit lung volume. These measurements enable calculation of standard morphometric characteristics, such as mean linear intercept and surface-to-volume ratio. Results:Noninvasive 3 He lung morphometry was used to detect alterations in acinar structure in smokers with normal PFT fi ndings. When compared with smokers with the largest forced expiratory volume in 1 second (FEV 1 ) to forced vital capacity (FVC) ratio, those with chronic obstructive pulmonary disease had signifi cantly reduced alveolar depth (0.07 mm vs 0.13 mm) and enlarged acinar ducts (0.36 mm vs 0.3 mm). The mean alveolar geometry measurements in the healthiest subjects were in excellent quantitative agreement with literature values obtained by using invasive techniques (acinar duct radius, 0.3 mm; alveolar depth, 0.14 mm at 1 L above functional residual capacity).3 He lung morphometry depicted greater abnormalities than did PFT and CT. No adverse events were associated with inhalation of 3 He gas. Conclusion:3 He lung morphometry yields valuable noninvasive insight into early emphysematous changes in alveolar geometry with increased sensitivity compared with conventional techniques.

).q RSNA, 2014 Purpose:To quantify regional lung ventilation in healthy volunteers and patients with severe asthma (both before and after thermoplasty) by using a combination of helium 3 ( 3 He) magnetic resonance (MR) imaging and computed tomography (CT), with the intention of developing more effective image-guided treatments for obstructive lung diseases. Materials andMethods:With approval of the local institutional review board, informed consent, and an Investigational New Drug Exemption, six healthy volunteers and 10 patients with severe asthma were imaged in compliance with HIPAA regulations by using both multidetector CT and 3He MR imaging. Individual bronchopulmonary segments were labeled voxel by voxel from the CT images and then registered to the Results:Ventilation measures for healthy volunteers yielded smaller segment-to-segment variation (mean SVP, 100% 6 18 [standard deviation]) than did the measures for patients with severe asthma (mean SVP, 97% 6 23). Patients with asthma also demonstrated larger segmental defect percentages (median, 13.5%; interquartile range, 8.9%-17.8%) than healthy volunteers (median, 6%; interquartile range, 5.6%-6.3%). These quantitative results confirm what is visually observed on the 3 He images. A Spearman correlation of r = 20.82 was found between the change in whole-lung defect percentage and the number of days between final treatment and second 3 He imaging. Conclusion:Regional quantification of lung ventilation is indeed feasible and may be a useful technique for image-guided treatment of obstructive lung diseases, such as bronchial thermoplasty for severe asthma. In these patients, ventilation defects decreased as a function of time after treatment.q RSNA, 2014

The recently developed technique of lung morphometry using hyperpolarized (3)He diffusion magnetic resonance (MR) (Yablonskiy DA, Sukstanskii AL, Woods JC, Gierada DS, Quirk JD, Hogg JC, Cooper JD, Conradi MS. J Appl Physiol 107: 1258-1265, 2009) permits in vivo study of lung microstructure at the alveolar level. Originally proposed for human lungs, it also has the potential to study small animals. The technique relies on theoretical developments in the area of gas diffusion in lungs linking the diffusion attenuated MR signal to the lung microstructure. To adapt this technique to small animals, certain modifications in MR protocol and data analysis are required, reflecting the smaller size of mouse alveoli and acinar airways. This is the subject of the present paper. Herein, we established empirical relationships relating diffusion measurements to geometrical parameters of lung acinar airways with dimensions typical for mice and rats by using simulations of diffusion in the airways. We have also adjusted the MR protocol to acquire data with much shorter diffusion times compared with humans to accommodate the substantially smaller acinar airway length. We apply this technique to study mouse lungs ex vivo. Our MR-based measurements yield mean values of lung surface-to-volume ratio of 670 cm(-1), alveolar density of 3,200 per mm(3), alveolar depth of 55 μm, and mean chord length of 62 μm, all consistent with published data obtained histologically in mice by unbiased methods. The proposed technique can be used for in vivo experiments, opening a door for longitudinal studies of lung morphometry in mice and other small animals.

Despite decades of research into the mechanisms of lung inflation and deflation, there is little consensus about whether lung inflation occurs due to the recruitment of new alveoli or by changes in the size and/or shape of alveoli and alveolar ducts. In this study we use in vivo (3)He lung morphometry via MRI to measure the average alveolar depth and alveolar duct radius at three levels of inspiration in five healthy human subjects and calculate the average alveolar volume, surface area, and the total number of alveoli at each level of inflation. Our results indicate that during a 143 ± 18% increase in lung gas volume, the average alveolar depth decreases 21 ±5%, the average alveolar duct radius increases 7 ± 3%, and the total number of alveoli increases by 96 ± 9% (results are means ± SD between subjects; P < 0.001, P < 0.01, and P < 0.00001, respectively, via paired t-tests). Thus our results indicate that in healthy human subjects the lung inflates primarily by alveolar recruitment and, to a lesser extent, by anisotropic expansion of alveolar ducts.

The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized (3)He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized (3)He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger.

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