Imaging techniques for small animal models of pulmonary disease: MR microscopy

Abstract

In vivo magnetic resonance microscopy (MRM) of the small animal lung has become a valuable research tool, especially for preclinical studies. MRM offers a noninvasive and nondestructive tool for imaging small animals longitudinally and at high spatial resolution. We summarize some of the technical and biologic problems and solutions associated with imaging the small animal lung and describe several important pulmonary disease applications. A major advantage of MR is direct imaging of the gas spaces of the lung using breathable gases such as helium and xenon. When polarized, these gases become rich MR signal sources. In animals breathing hyperpolarized helium, the dynamics of gas distribution can be followed and airway constrictions and obstructions can be detected. Diffusion coefficients of helium can be calculated from diffusion-sensitive images, which can reveal micro-structural changes in the lungs associated with pathologies such as emphysema and fibrosis. Unlike helium, xenon in the lung is absorbed by blood and exhibits different frequencies in gas, tissue, or erythrocytes. Thus, with MR imaging, the movement of xenon gas can be tracked through pulmonary compartments to detect defects of gas transfer. MRM has become a valuable tool for studying morphologic and functional changes in small animal models of lung diseases.

Figure 1

A. Apparatus for in vivo imaging showing a 23-gram mouse in an imaging cradle with ECG and temperature leads attached, with a 3-cm inner diameter, dual-frequency imaging (¹H-³He) MR imaging coil in the background. B. Ventilation system near the bore of the 2 T MR small animal imaging system, after the mouse and coil have been inserted into the magnet.

Figure 2

Example of a high-resolution proton morphologic image of a rat lung using the 2T system shown in Figure 1. The parenchyma signal intensity has been enhanced by an infusion of gadolinium chelate (Gd) contrast agent (Magnevist Berlex Imaging, Wayne, NJ). These 6 slices are taken from an isotropic dataset with resolution of 117 × 117 × 117 μm³. Reprinted with permission from (Johnson et al., 2001).

Figure 3

Schematic representation of hyperpolarization by optical pumping and spin exchange. ³He and ¹²⁹Xe nuclei acquire a high degree of nuclear magnetic alignment through angular momentum transfer from laser photons to vaporized Rubidium (Rb) and then spin exchange with ³He/¹²⁹Xe. In this hyperpolarized state, these gases enhance the MRI signal by roughly 10⁵, more than enough to overcome the low density and enable the gases to be imaged with exquisite resolution.

Figure 4

A schematic of a gas polarizer. Laser light is circularly polarized so that all photons carry +1 quantum of angular momentum. The laser light is absorbed by an Rb vapor in the optical gas cell, thus aligning the valence electrons of all the Rb atoms with the weak magnetic field provided by the Helmholtz coils. Collisions between polarized Rb atoms and ³He or ¹²⁹Xe atoms transfer the alignment to the ³He or ¹²⁹Xe nuclei, as illustrated in Figure 3. The oven elevates the gas cell temperature to about 200°C to vaporize the Rb. The sense coil monitors the extent of gas polarization. (Reprinted with permission from (Kadlecek et al., 2002).

Figure 5

3D ³He MR images of a 25-gram mouse. The resolution is 125 × 125 × 1000 μm. The image required 5.8 minutes to acquire and consumed 92 ml of hyperpolarized ³He.

Figure 6

These ³He images illustrate different representations and image acquisition strategies. (A) Maximum intensity projection (MIP) of all coronal slices in the three-dimensional dataset shown in Figure 5. This MIP representation acquired in 5.8 minutes more clearly shows major lobar airways. (B) A single central slice from the same dataset as in Figure 4. (C) A full dorso-ventral projection image from a different mouse required only 12 seconds to acquire and consumed only 2 ml of HP ³He. However, this image shows less detail of the airways. These images illustrate the trade-offs that are made in image acquisition and temporal resolution to derive the desired information.

Figure 7

The progress in xenon ventilation imaging in the rat. (A) One of the first ¹²⁹Xe images made in this laboratory in 1998 with 0.84 × 0.84 mm² resolution and SNR of about 3. (B–D) show progressively better image quality as polarization, gas delivery technology, and MR acquisition strategies have been improved. Our current standard ¹²⁹Xe image (D) with resolution of 0.31 × 0.31 mm² and an SNR of about 20. Continued progress in these areas should lead to even further improvement in image quality.

Figure 8

(A) A schematic representation of the different molecular environments experienced by ¹²⁹Xe in the lung (left) and (right) schematic summary of functional compartments: air space (0), barrier (197) (alveolar epithelium, interstitium, capilliary endothelium, plasma), and red blood cells (RBCs) (211). (B) A spectrum of ¹²⁹Xe in the rat lung. The spectrum exhibits 3 distinct resonances at 211 ppm (RBC), 197 ppm (barrier space), and 0 ppm (air space). The ability to discriminate ¹²⁹Xe in these distinct environments creates a unique tool to measure the transfer dynamics of ¹²⁹Xe among these various compartments, thereby supporting measurement of micron-scale thickening of the alveolar-capillary barrier, such as may be present in inflammation or fibrosis.

Figure 9

¹²⁹Xe images in three different pulmonary compartments—gas space (A, D), barrier (B, E), and RBC (C, F). The top panels (A–C) depict a control rat. The bottom panels (D–F) show a rat with left lung fibrosis from a unilateral instillation of bleomycin. In the fibrotic lung, there is full absorption into the “barrier” tissue space (E) and a dramatic lack of ¹²⁹Xe signal in the RBC compartment (arrows) (F). We hypothesize that the lack of RBC signal is due to the increased diffusion time required for ¹²⁹Xe to traverse the thickened blood–gas barrier.