Relationship between Pulmonary Gas Exchange Function and Brain Uptake Dynamics Investigated with Hyperpolarized 129Xe MR Imaging and Spectroscopy in a Murine Model of Chronic Obstructive Pulmonary Disease

Abstract

Purpose: Chronic obstructive pulmonary disease (COPD) is a complex multisystem disease associated with comorbidities outside the lungs. The aim of this study was to measure changes in metrics of pulmonary gas exchange function and brain tissue metabolism in a mouse model of COPD using hyperpolarized ¹²⁹Xe (HP ¹²⁹Xe) MRI/MR spectroscopy (MRS) and investigate the relationship between the metrics of lung and brain.

Methods: COPD phenotypes were induced in 15 mice by 6-week administration of cigarette smoke extract (CSE) and lipopolysaccharide (LPS). A separate negative control (NC) group was formed of 6 mice administered with saline for 6 weeks. After these 6-week administrations, the pulmonary gas exchange function parameter f_D (%) and the rate constant, α (s^-1), which are composed of the cerebral blood flow F_i and the longitudinal relaxation rate 1/T_1i in brain tissue, were evaluated by HP ¹²⁹Xe MRI/MRS.

Results: The f_D of CSE-LPS mice was significantly lower than that of NC mice, which was in parallel with an increase in bronchial wall thickness. The α in the CSE-LPS mice decreased with the decrease of f_D in contrast to the trend in the NC mice. To further elucidate the opposed trend, the contribution of T_1i was separately determined by measuring F_i. The T_1i in the CSE-LPS mice was found to correlate negatively with f_D as opposed to the positive trend in the NC mice. The opposite trend in T_1i between CSE-LPS and NC mice suggests hypoxia in the brain, which is induced by the impaired oxygen uptake as indicated by the reduced f_D.

Conclusion: This study demonstrates the feasibility of using HP ¹²⁹Xe MRI/MRS to study pathological mechanisms of brain dysfunction in comorbidities with COPD.

Keywords: brain uptake dynamics; hyperpolarized 129Xe; murine chronic obstructive pulmonary disease; pulmonary gas exchange function.

Fig. 1

Relationship between pulmonary gas exchange (f_D) and brain uptake function (α and F_i) measured based on the HP ¹²⁹Xe uptake model. HP ¹²⁹Xe, hyperpolarized ¹²⁹Xe.

Fig. 2

Example f_D maps evaluated by HP ¹²⁹Xe MRI (a) and profiles of saturation recovery of HP ¹²⁹Xe in brain (b) of NC and CSE-LPS mice. The f_D values were 6.9% for NC mouse and 4.4% for CSE-LPS mouse, respectively. CSE-LPS, cigarette smoke extract and lipopolysaccharide; HP ¹²⁹Xe, hyperpolarized ¹²⁹Xe; NC, negative control.

Fig. 3

Box plots of comparison of f_D (a), α (b), F_i (c), and T_1i (d) between CSE-LPS and NC mice (**: P < 0.01). CSE-LPS, cigarette smoke extract and lipopolysaccharide; NC, negative control.

Fig. 4

Representative examples of histology slides obtained from NC and CSE-LPS mice (a), box plots of comparison of bronchial wall thickness (h) of the NC and CSE-LPS mice (b) (**: P < 0.01), and correlation between the bronchial wall thickness (h) and f_D (r² = 0.81 and P < 0.01). CSE-LPS, cigarette smoke extract and lipopolysaccharide; NC, negative control.

Fig. 5

Relationship between α and f_D of NC and CSE-LPS groups. Correlation: r² = 0.71 and P < 0.01 for the CSE-LPS mice, r² = 0.79 and P < 0.01 for the NC mice. CSE-LPS, cigarette smoke extract and lipopolysaccharide; NC, negative control.

Fig. 6

Relationship between F_i and f_D of NC and CSE-LPS groups. Correlation: r² = 0.93 and P < 0.01 for the CSE-LPS mice, r = 0.09 and P > 0.05 for the NC mice. CSE-LPS, cigarette smoke extract and lipopolysaccharide; NC, negative control.

Fig. 7

Relationship between T_1i and f_D of NC and CSE-LPS groups. Correlation: r² = 0.92 and P < 0.01 for the CSE-LPS mice, r² = 0.75 and P < 0.05 for the NC mice. CSE-LPS, cigarette smoke extract and lipopolysaccharide; NC, negative control.