Monitoring in vivo changes in lung microstructure with ³He MRI in Sendai virus-infected mice

Abstract

Recently, a Sendai virus (SeV) model of chronic obstructive lung disease has demonstrated an innate immune response in mouse airways that exhibits similarities to the chronic airway inflammation in human chronic obstructive pulmonary disease (COPD) and asthma, but the effect on distal lung parenchyma has not been investigated. The aim of our study is to image the time course and regional distribution of mouse lung microstructural changes in vivo after SeV infection. (1)H and (3)He diffusion magnetic resonance imaging (MRI) were successfully performed on five groups of C57BL/6J mice. (1)H MR images provided precise anatomical localization and lung volume measurements. (3)He lung morphometry was implemented to image and quantify mouse lung geometric microstructural parameters at different time points after SeV infection. (1)H MR images detected the SeV-induced pulmonary inflammation in vivo; spatially resolved maps of acinar airway radius R, alveolar depth h, and mean linear intercept Lm were generated from (3)He diffusion images. The morphometric parameters R and Lm in the infected group were indistinguishable from PBS-treated mice at day 21, increased slightly at day 49, and were increased with statistical significance at day 77 (p = 0.02). Increases in R and Lm of infected mice imply that there is a modest increase in alveolar duct radius distal to airway inflammation, particularly in the lung periphery, indicating airspace enlargement after virus infection. Our results indicate that (3)He lung morphometry has good sensitivity in quantifying small microstructural changes in the mouse lung and that the Sendai mouse model has the potential to be a valid murine model of COPD.

Fig. 1.

Representative set of ¹H magnetic resonance (MR) images of PBS 49 day mouse (top) and corresponding set of HP ³He ventilation images (bottom).

Fig. 2.

One representative ¹H MR image (top left) and corresponding ³He ventilation image (bottom right) of a Sendai (SeV) 77 day mouse. Microscope images correspond to the regions outlined in MR images. Lung parenchyma in the blue square is relatively normal, whereas the red square shows significant inflammation induced by SeV. This is clearly shown by the higher ¹H signal and lower ³He signal in the red square compared with the blue one.

Fig. 3.

Representative parametric (R, h, and Lm) maps obtained from a SeV 21 day mouse. Major airways are excluded. Color bar shows the range of the parameters (R, h, and Lm) from 35 to 135 μm.

Fig. 4.

Representative R, Lm maps and transverse ³He MR ventilation images from groups of PBS 49 day, PBS 84 day, SeV 21 day, SeV 49 day, SeV 77 day at the same slice location. Elevation of R and Lm in the periphery increases with time after SeV infection.

Fig. 5.

Percentages of voxels with R above a range of the threshold values for all groups of mice. Curves for control (brown dashed line), PBS 49 day (purple dashed line) and PBS 84 day (blue dashed line) have lower percentage values compared with SeV-infected groups (solid line) at high value range of R (100–105 μm shown here), indicating there are more pixel with higher R values in the SeV-infected groups than the control and PBS groups.

Fig. 6.

Linear regression of lung volumes measured by ³He-MR and ¹H-MR methods.