Hyperpolarized gas diffusion MRI of biphasic lung inflation in short- and long-term emphysema models

Abstract

During lung inflation, airspace dimensions are affected nonlinearly by both alveolar expansion and recruitment, potentially confounding the identification of emphysematous lung by hyperpolarized helium-3 diffusion magnetic resonance imaging (HP MRI). This study aimed to characterize lung inflation over a broad range of inflation volume and pressure values in two different models of emphysema, as well as in normal lungs. Elastase-treated rats (n = 7) and healthy controls (n = 7) were imaged with HP MRI. Gradual inflation was achieved by incremental changes to both inflation volume and airway pressure. The apparent diffusion coefficient (ADC) was measured at each level of inflation and fitted to the corresponding airway pressures as the second-order response equation, with minimizing residue (χ² < 0.001). A biphasic ADC response was detected, with an initial ADC increase followed by a decrease at airway pressures >18 cmH₂O. Discrimination between treated and control rats was optimal when airway pressure was intermediate (between 10 and 11 cmH₂O). Similar findings were confirmed in mice following long-term exposure to cigarette smoke, where optimal discrimination between treated and healthy mice occurred at a similar airway pressure as in the rats. We subsequently explored the evolution of ADC measured at the intermediate inflation level in mice after prolonged smoke exposure and found a significant increase (P < 0.01) in ADC over time. Our results demonstrate that measuring ADC at intermediate inflation enhances the distinction between healthy and diseased lungs, thereby establishing a model that may improve the diagnostic accuracy of future HP gas diffusion studies.

Keywords: apparent diffusion coefficient; hyperpolarized gas magnetic resonance imaging; lung dynamics; lung physiology.

Fig. 1.

A: schematic diagram of the ventilation protocol used to measure apparent diffusion coefficient (ADC) at end inspiration. Prior to the imaging sequence, lungs were ventilated with ⁴He:O₂ at a 4:1 ratio. Then a single high volume “sigh” breath was delivered with hyperpolarized ³He:O₂ at the same ratio. This was followed by three hyperpolarized ³He:O₂ breaths at the desired inflation volume, with an inspiratory hold after the last inspiration during which ADC was measured. B: graded inflation levels were reached by increasing inspiratory time (IT), while maintaining a constant inspiratory flow. PIP, peak inspiratory pressure.

Fig. 2.

Representative images of ³He spin density maps and corresponding ADC maps obtained at increasing inflation volume and corresponding PIP in healthy vs. elastase-treated rats.

Fig. 3.

Plots of ADC vs. PIP in each individual control rat (top) and elastase-treated (bottom) included in the study. Each ADC vs. PIP plot was fitted with a second-order response system.

Fig. 4.

A: summary statistics (median, interquartile range, and extremes of the distribution) of fitted ADC values in healthy (black) vs. elastase-treated (red) rats. B: P values of the comparisons between the two groups are shown in at all tested incremental PIP levels. C: higher slope of the ADC vs. PIP curve. D: lower PIP corresponding to the maximum ADC suggest higher compliance in elastase-treated vs. normal rats.

Fig. 5.

Representative histology slices of elastase-treated (A) and control (B) rats. Correlation between ADC values and histological metrics or airspace morphometry: mean airspace diameter D₀ (C), and second-order moments D₂ (D) of the diameter distribution.

Fig. 6.

Left: summary statistics (median, interquartile range, and extremes of the distribution) of fitted ADC values in naïve (green), control (blue) vs. smoke exposure (red). Right: panels show P values of the comparisons between mice after smoke exposure vs. control and naïve mice, plotted against incremental inflation levels.

Fig. 7.

Summary statistics (median, interquartile range, and extremes of the distribution) of ADC value in 6-mo naïve (n = 7), 6-mo control (n = 8), 6-mo smoke (n = 6), 18-mo naïve (n = 8), 18-mo control (n = 7), and 18-mo smoke (n = 6) mouse cohorts.