Radical-induced hetero-nuclear mixing and low-field 13C relaxation in solid pyruvic acid.

Radicals serve as a source of polarization in dynamic nuclear polarization, but may also act as polarization sink, in particular at low field. Additionally, if the couplings between the electron spins and different nuclear reservoirs are stronger than any of the reservoirs' couplings to the lattice, radicals can mediate hetero-nuclear polarization transfer. Here, we report radical-enhanced 13C relaxation in pyruvic acid doped with trityl. Up to 40 K, we find a linear carbon T1 field dependence between 5 mT and 2 T. We model the dependence quantitatively, and find that the presence of trityl accelerates direct hetero-nuclear polarization transfer at low fields, while at higher fields 13C relaxation is diffusion limited. Measurements of hetero-nuclear polarization transfer up to 600 mT confirm the predicted radical-mediated proton-carbon mixing.

Radical-Induced Low-Field 1H Relaxation in Solid Pyruvic Acid Doped with Trityl-OX063.

In dynamic nuclear polarization (DNP), radicals such as trityl provide a source for high nuclear spin polarization. Conversely, during the low-field transfer of hyperpolarized solids, the radicals' dipolar or Non-Zeeman reservoir may act as a powerful nuclear polarization sink. Here, we report the low-temperature proton spin relaxation in pyruvic acid doped with trityl, for fields from 5 mT to 2 T. We estimate the heat capacity of the radical Non-Zeeman reservoir experimentally and show that a recent formalism by Wenckebach yields a parameter-free, yet quantitative model for the entire field range.

The validity of shortened multiple-breath washout testing using sulfur hexafluoride in the assessment of patients with COPD.

INTRODUCTION: COPD affects the small airways and is associated with ventilation heterogeneity. There are little data on the multiple-breath washout (MBW) in patients with COPD, particularly the variability over 8 weeks, using a shortened sulfur hexafluoride (SF6) washout. This work evaluated the repeatability of the lung clearance index (LCI)1/40 and LCI1/20 among subjects with COPD and compared to spirometry and clinical markers. METHODS: The MBW was performed on patients with COPD to determine ventilation heterogeneity globally (LCI), at conductive (Scond) and acinar (Sacin) levels. The LCI was repeated in triplicate and measured at a traditional 1/40th washout and retrofitted to a shortened 1/20th end tidal SF6 concentration washout. Tests were repeated after 20 min and 8  weeks to determine within and between visit repeatability and compared with spirometry. RESULTS: Eighty-four subjects were recruited to perform LCI and spirometry with 20 subjects performing the repeatability protocol. There were weak correlations between forced expiratory volume in 1 s ( FEV1) per cent predicted and LCI1/40th r=-0.311 (p=0.02), and LCI1/20th r=-0.40 (p<0.01). The LCI demonstrated excellent within and good between visit repeatability for both a 1/40th and 1/20th washout (intraclass correlation coefficient (ICC)≥0.80). There was a statistically significant strong correlation between LCI1/40th and a shortened LCI1/20 of 0.86 (p<0.01). CONCLUSIONS: The LCI is repeatable within and between visits. There are weak correlations with measures of spirometry. A shortened LCI1/20th starting concentration correlates highly with a 1/40th washout, which may encourage clinical use.

Characterising the role of small airways in severe asthma using low frequency forced oscillations: A combined computational and clinical approach.

BACKGROUND: Within asthma, the small airways (≤2 mm in diameter) play an important role in pathophysiology. Using a combined clinical-computational approach, we sought to more precisely evaluate the contribution of the small airways to deep-breath induced airway dilation (in the absence of bronchial challenge), which may be impaired in severe asthma. METHODS: A patient-based computational model of the FOT was used to examine the sensitivity and specificity of FOT signals to small airways constriction at frequencies of 2 & 8 Hz. A clinical study of moderate to severe asthmatics (n = 24), and healthy volunteers (n = 10) was performed to evaluate correlations between baseline and post deep inspiration (following bronchodilator withhold and in the absence of prior bronchial challenge) forced oscillation technique (FOT) responses (at 2Hz and 8Hz) and asthma treatment intensity, spirometry, airway hyper-responsiveness and airway inflammation. RESULTS: Computational modelling demonstrated that baseline resistance measures at 2Hz are both sensitive and specific to anatomical narrowing in the small airways. Furthermore, small airways resistance was significantly increased in asthmatics compared to health. Despite these differences, there were no noticeable differences between asthmatics and healthy volunteers in resistive measures following deep inspiration (DI) and DI responses of small airways were amplified in the presence of spirometry defined airflow limitation. CONCLUSIONS: These results suggest that the small airways demonstrate increased resistance in moderate-to-severe asthma but dilate normally in response to deep inspirations in the absence of bronchial challenge. This suggests that effective targeting of the small airways is required to achieve functional improvements in moderate-severe asthmatic patients.

Lung Computational Models and the Role of the Small Airways in Asthma.

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Comparison of Forced and Impulse Oscillometry Measurements: A Clinical Population and Printed Airway Model Study.

The use of commercialised forced oscillation (FOT) devices to assess impedance in obstructive diseases such as asthma has gained popularity. However, it has yet to be fully established whether resistance and reactance measurements are comparable across different FOT devices, particularly in disease. We compared two commercially available FOT devices: Impulse Oscillometry (IOS) and TremoFlo FOT (Thorasys) in a) clinical adult population of healthy controls (n = 14), asymptomatic smokers (n = 17) and individuals with asthma (n = 73) and b) a 3D printed CT-derived airway tree model resistance, as well as a 3 L standardised volume reactance. Bland-Altman Plots and linear regressions were used to evaluate bias between the devices. Resistance measurements at both 5 and 20 Hz were numerically higher with IOS compared to FOT, with evidence of small and statistically significant proportional systematic bias and a positive Bland-Altman regression slope at both 5 and 20 Hz. In contrast, the IOS device recorded reactances that were less negative at both 5 Hz and 20 Hz and significantly smaller reactance areas when compared to TremoFlo. Larger statistically significant proportional systematic biases were demonstrated with both reactance at 5 Hz and reactance area (AX) between the devices with a negative Bland-Altman regression slope. The printed airway resistance and standardised volume reactance confirmed the observations seen in patients. We have demonstrated that the impulse oscillation system and TremoFlo FOT demonstrate comparative bias, particularly when comparing airway reactance in patients. Our results highlight the need for further standardisation across FOT measurement devices, specifically using variable test loads for reactance standardisation.

Closed circuit rebreathing to achieve inert gas wash-in for multiple breath wash-out.

Multiple breath wash-out (MBW) testing requires prior wash-in of inert tracer gas. Wash-in efficiency can be enhanced by a rebreathing tracer in a closed circuit. Previous attempts to deploy this did not account for the impact of CO2 accumulation on patients and were unsuccessful. We hypothesised that an effective rebreathe wash-in could be delivered and it would not alter wash-out parameters. Computer modelling was used to assess the impact of the rebreathe method on wash-in efficiency. Clinical testing of open and closed circuit wash-in-wash-out was performed in healthy controls and adult patients with cystic fibrosis (CF) using a circuit with an effective CO2 scrubber and a refined wash-in protocol. Wash-in efficiency was enhanced by rebreathing. There was no difference in mean lung clearance index between the two wash-in methods for controls (6.5 versus 6.4; p=0.2, n=12) or patients with CF (10.9 versus 10.8; p=0.2, n=19). Test time was reduced by rebreathe wash-in (156 versus 230 s for CF patients, p<0.001) and both methods were well tolerated. End wash-in CO2 was maintained below 2% in most cases. Rebreathe-wash-in is a promising development that, when correctly deployed, reduces wash-in time and facilitates portable MBW testing. For mild CF, wash-out outcomes are equivalent to an open circuit.

Correction: Low-field thermal mixing in [1-(13)C] pyruvic acid for brute-force hyperpolarization.

Correction for 'Low-field thermal mixing in [1-(13)C] pyruvic acid for brute-force hyperpolarization' by David T. Peat et al., Phys. Chem. Chem. Phys., 2016, 18, 19173-19182.

Low-field thermal mixing in [1-(13)C] pyruvic acid for brute-force hyperpolarization.

We detail the process of low-field thermal mixing (LFTM) between (1)H and (13)C nuclei in neat [1-(13)C] pyruvic acid at cryogenic temperatures (4-15 K). Using fast-field-cycling NMR, (1)H nuclei in the molecule were polarized at modest high field (2 T) and then equilibrated with (13)C nuclei by fast cycling (∼300-400 ms) to a low field (0-300 G) that activates thermal mixing. The (13)C NMR spectrum was recorded after fast cycling back to 2 T. The (13)C signal derives from (1)H polarization via LFTM, in which the polarized ('cold') proton bath contacts the unpolarised ('hot') (13)C bath at a field so low that Zeeman and dipolar interactions are similar-sized and fluctuations in the latter drive (1)H-(13)C equilibration. By varying mixing time (tmix) and field (Bmix), we determined field-dependent rates of polarization transfer (1/τ) and decay (1/T1m) during mixing. This defines conditions for effective mixing, as utilized in 'brute-force' hyperpolarization of low-γ nuclei like (13)C using Boltzmann polarization from nearby protons. For neat pyruvic acid, near-optimum mixing occurs for tmix∼ 100-300 ms and Bmix∼ 30-60 G. Three forms of frozen neat pyruvic acid were tested: two glassy samples, (one well-deoxygenated, the other O2-exposed) and one sample pre-treated by annealing (also well-deoxygenated). Both annealing and the presence of O2 are known to dramatically alter high-field longitudinal relaxation (T1) of (1)H and (13)C (up to 10(2)-10(3)-fold effects). Here, we found smaller, but still critical factors of ∼(2-5)× on both τ and T1m. Annealed, well-deoxygenated samples exhibit the longest time constants, e.g., τ∼ 30-70 ms and T1m∼ 1-20 s, each growing vs. Bmix. Mixing 'turns off' for Bmix > ∼100 G. That T1m≫τ is consistent with earlier success with polarization transfer from (1)H to (13)C by LFTM.

Use of Nuclear Spin Noise Spectroscopy to Monitor Slow Magnetization Buildup at Millikelvin Temperatures.

At ultralow temperatures, longitudinal nuclear magnetic relaxation times become exceedingly long and spectral lines are very broad. These facts pose particular challenges for the measurement of NMR spectra and spin relaxation phenomena. Nuclear spin noise spectroscopy is used to monitor proton spin polarization buildup to thermal equilibrium of a mixture of glycerol, water, and copper oxide nanoparticles at 17.5 mK in a static magnetic field of 2.5 T. Relaxation times determined in such a way are essentially free from perturbations caused by excitation radiofrequency pulses, radiation damping, and insufficient excitation bandwidth. The experimental spin-lattice relaxation times determined on resonance by saturation recovery with spin noise detection are consistently longer than those determined by using pulse excitation. These longer values are in better accordance with the expected field dependence trend than those obtained by on-resonance experiments with pulsed excitation.

Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized (3)helium magnetic resonance.

BACKGROUND: The multiple-breath inert gas washout parameter acinar ventilation heterogeneity (Sacin) is thought to be a marker of acinar airway involvement but has not been validated by using quantitative imaging techniques in asthmatic patients. OBJECTIVE: We aimed to use hyperpolarized (3)He diffusion magnetic resonance at multiple diffusion timescales and quantitative computed tomographic (CT) densitometry to determine the nature of acinar airway involvement in asthmatic patients. METHODS: Thirty-seven patients with asthma and 17 age-matched healthy control subjects underwent spirometry, body plethysmography, multiple-breath inert gas washout (with the tracer gas sulfur hexafluoride), and hyperpolarized (3)He diffusion magnetic resonance. A subset of asthmatic patients (n = 27) underwent quantitative CT densitometry. RESULTS: Ninety-four percent (16/17) of patients with an increased Sacin had Global Initiative for Asthma treatment step 4 to 5 asthma, and 13 of 17 had refractory disease. The apparent diffusion coefficient (ADC) of (3)He at 1 second was significantly higher in patients with Sacin-high asthma compared with that in healthy control subjects (0.024 vs 0.017, P < .05). Sacin correlated strongly with ADCs at 1 second (R = 0.65, P < .001) but weakly with ADCs at 13 ms (R = 0.38, P < .05). ADCs at both 13 ms and 1 second correlated strongly with the mean lung density expiratory/inspiratory ratio, a CT marker of expiratory air trapping (R = 0.77, P < .0001 for ADCs at 13 ms; R = 0.72, P < .001 for ADCs at 1 second). CONCLUSION: Sacin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomic nature and mechanistic role in patients with severe asthma requires further evaluation.

Breastfeeding, lung volumes and alveolar size at school-age.

BACKGROUND: Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma. METHODS: We analysed data from 111 children and young adults aged 11-21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of (3)Helium ((3)He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1-4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders. RESULTS: We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels. CONCLUSIONS: Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.

High polarization of nuclear spins mediated by nanoparticles at millikelvin temperatures.

Nuclear magnetic resonance (NMR) techniques are extensively used in many areas of basic and clinical research, as well as in diagnostic medicine. However, NMR signals are intrinsically weak, and this imposes substantial constraints on the amounts and concentrations of materials that can be detected. The signals are weak because of the low energies characteristic of NMR and the resulting very low (typically 0.0001-0.01%) polarization of the nuclear spins. Here, we show that exposure to very low temperatures and high magnetic fields, in conjunction with nanoparticle-mediated relaxation enhancement, can be used to generate extremely high nuclear polarization levels on a realistic timescale; with copper nanoparticles at 15 mK and 14 T, (13)C polarization grew towards its equilibrium level of 23% with an estimated half-time of about 60 hours. This contrasts with a (13)C half-time of at least one year in the presence of aluminium nanoparticles. Cupric oxide nanoparticles were also effective relaxation agents. Our findings lead us to suspect that the relaxation may be mediated, at least in part, by the remarkable magnetic properties that some nanoparticle preparations can display. This methodology offers prospects for achieving polarization levels of 10-50% or more for many nuclear species, with a wide range of potential applications in structural biology and medicine.

Achievement of high nuclear spin polarization using lanthanides as low-temperature NMR relaxation agents.

Many approaches are now available for achieving high levels of nuclear spin polarization. One of these methods is based on the notion that as the temperature is reduced, the equilibrium nuclear polarization will increase, according to the Boltzmann distribution. The main problem with this approach is the length of time it may take to approach thermal equilibrium at low temperatures, since nuclear relaxation times (characterized by the spin-lattice relaxation time T1) can become very long. Here, we show, by means of relaxation time measurements of frozen solutions, that selected lanthanide ions, in the form of their chelates with DTPA, can act as effective relaxation agents at low temperatures. Differential effects are seen with the different lanthanides that were tested, holmium and dysprosium showing highest relaxivity, while gadolinium is ineffective at temperatures of 20 K and below. These observations are consistent with the known electron-spin relaxation time characteristics of these lanthanides. The maximum relaxivity occurs at around 10 K for Ho-DTPA and 20 K for Dy-DTPA. Moreover, these two agents show only modest relaxivity at room temperature, and can thus be regarded as relaxation switches. We conclude that these agents can speed up solid state NMR experiments by reducing the T1 values of the relevant nuclei, and hence increasing the rate at which data can be acquired. They could also be of value in the context of a simple low-cost method of achieving several-hundred-fold improvements in polarization for experiments in which samples are pre-polarized at low temperatures, then rewarmed and dissolved immediately prior to analysis.

Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance.

RATIONALE: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. OBJECTIVES: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. METHODS: We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n = 61); (2) mild preterm (32-36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. MEASUREMENTS AND MAIN RESULTS: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm(2)/second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. CONCLUSIONS: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.

Preparation of highly polarized nuclear spin systems using brute-force and low-field thermal mixing.

Over the years, several strategies have been developed for generating highly polarized nuclear spin systems, including dynamic nuclear polarization, optical pumping, and methods exploiting parahydrogen. Here, we present an alternative strategy, using an enhanced 'brute-force' approach (i.e. exposure to low temperatures and high applied magnetic fields). The main problem with this approach is that it may take an excessively long time for the nuclear polarization to approach thermal equilibrium at low temperatures, since nuclear relaxation becomes exceedingly slow due to the loss of molecular motion. We show that low-field thermal mixing can alleviate the problem by increasing the rate at which slowly-relaxing nuclei reach equilibrium. More specifically, we show that polarization can be transferred from a relatively rapidly relaxing (1)H reservoir to more slowly relaxing (13)C and (31)P nuclei. The effects are particularly dramatic for the (31)P nuclei, which in experiments at a temperature of 4.2 K and a field of 2 T show a 75-fold enhancement in their effective rate of approach to equilibrium, and an even greater (150-fold) enhancement in the presence of a relaxation agent. The mixing step is also very effective in terms of the amount of polarization transferred-70-90% of the maximum theoretical value in the experiments reported here. These findings have important implications for brute-force polarization, for the problem becomes one of how to relax the solvent protons rather than individual more slowly-relaxing nuclei of interest. This should be a much more tractable proposition, and offers the additional attraction that a wide range of nuclear species can be polarized simultaneously. We further show that the (1)H reservoir can be tapped repeatedly through a number of consecutive thermal mixing steps, and that this could provide additional sensitivity enhancement in solid-state NMR.

Airway impedance entropy and exacerbations in severe asthma.

Variability of peak flow measurements has been related to clinical outcomes in asthma. We hypothesised that the entropy, or information content, of airway impedance over short time scales may predict asthma exacerbation frequency. 66 patients with severe asthma and 30 healthy control subjects underwent impulse oscillometry at baseline and following bronchodilator administration. On each occasion, airway impedance parameters were measured at 0.2-s intervals for 150 s, yielding a time series that was then subjected to sample entropy (SampEn) analysis. Airway impedance and SampEn of impedance were increased in asthmatic patients compared with healthy controls. In a logistic regression model, SampEn of the resistance at 5 Hz minus the resistance at 20 Hz, a marker of the fluctuation of the heterogeneity of airway constriction over time, was the variable most strongly associated with the frequent exacerbation phenotype (OR 3.23 for every 0.1 increase in SampEn). Increased airway impedance and SampEn of impedance are associated with the frequent exacerbation phenotype. Prospective studies are required to assess their predictive value.

Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance.

RATIONALE: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals. OBJECTIVES: We reexamined the current hypothesis using helium-3 ((3)He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent. METHODS: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7-21 years. Using (3)HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of (3)He at FRC (n = 109), and average diffusion distance of helium (X(rms)) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization. MEASUREMENTS AND MAIN RESULTS: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13-0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31-0.52). Similarly, increase of (X(rms)) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64-2.30) across the age range studied. CONCLUSIONS: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.

Acinar structure in symptom-free adults by Helium-3 magnetic resonance.

RATIONALE: The apparent diffusion coefficient of hyperpolarized (3)He in the lungs has been shown to correlate directly in animal models with the peripheral airspace size and can detect changes in lung microstructure. OBJECTIVES: To study in vivo the (3)He apparent diffusion coefficient and to demonstrate its sensitivity to changes in lung morphometry as a result of aging, exposure to cigarette smoke, and lung inflation. METHODS: We assessed the variation in the diffusion of hyperpolarized (3)He gas in the lungs by magnetic resonance techniques. Spirometric lung volumes were recorded. MEASUREMENTS: We measured the dependence of (3)He diffusion on age and on reported cigarette smoke exposure in 32 symptom-free adults. We also measured the dependence of the apparent diffusion coefficient on the degree of lung inflation. RESULTS: In healthy never-smokers, the apparent diffusion coefficient increased with age from 0.115 to 0.155 cm(2) . s(-1) at 20 and 70 yr, respectively, increased linearly with lung inflation and was independent of individual's lung size after correcting for age. For active and passive smokers, the apparent diffusion coefficient increased by up to 40% compared with never-smokers with mean values significantly higher (p=0.016 and p=0.0007, respectively). CONCLUSIONS: Peripheral airspace size increases with age and after exposure to smoke in healthy adults in agreement with previous histologic studies. We have confirmed in vivo that peripheral airspace size is independent of intersubject lung size.