High-resolution magnetic resonance colonography and dynamic contrast-enhanced magnetic resonance imaging in a murine model of colitis

Abstract

Inflammatory bowel disease, including ulcerative colitis, is characterized by persistent or recurrent inflammation and can progress to colon cancer. Colitis is difficult to detect and monitor noninvasively. The goal of this work was to develop a preclinical imaging method for evaluating colitis. Herein, we report improved MRI methods for detecting and characterizing colitis noninvasively in mice, using high-resolution in vivo MR images and dynamic contrast-enhanced MRI studies, which were confirmed by histologic studies in a murine model of colitis. C57Bl6/J male mice were treated with 2.5% dextran sulfate sodium in their drinking water for 5 days to induce colitis. MR images were acquired using a 9.4-T Bruker scanner from 5-25 days following dextran sulfate sodium treatment. In dynamic contrast-enhanced MRI studies, Gd uptake (K(trans)) and its distribution (v(e)) were measured in muscle and normal and inflamed colons after administering Gd-diethyltriaminepentaacetic acid (Gd-DTPA). T(2)-weighted MR images distinguished normal colon from diffusely thickened colonic wall occurring in colitis (P <0.0005) and correlated with histologic features. Values of K(trans) and v(e) obtained from dynamic contrast-enhanced MRI were also significantly different in inflamed colons compared to normal colon (P < 0.0005). The results demonstrate that both T(2)-weighted anatomic imaging and quantitative analysis of dynamic contrast-enhanced MRI data can successfully distinguish colitis from normal colon in mice.

FIG. 1

In vivo abdominal MR images of mice. a: This photograph shows how mice were set up inside a half birdcage coil (35mm in size) for in vivo imaging. The blue arrows indicate the length of the mouse body that can be scanned with this particular coil; the two ends of this coil are indicated by red arrows. b: An MR image is shown of a control, male C57Bl6/J mouse in the coronal plane that was acquired with a gradient echo sequence with an in-plane resolution of 117 microns. In this MR image, the air-filled colon is indicated by white arrows. The adjacent panel (b1) shows a high-resolution photograph of an excised colon from a control mouse; only the thin translucent wall is seen. c: An MR image in the coronal plane is shown of a colitis-bearing mouse; the brighter inflamed colon is markedly thickened, as indicated by yellow arrows. In the adjacent photograph (c1), the corresponding excised colon shows a thickened wall, ulcerated with scattered islands of residual mucosa.

FIG. 2

In vivo MR images of mouse colons. a,b: Gradient echo and spin echo images, respectively, are shown for a control mouse in the axial plane. Gradient echo images of a colitis-bearing mouse that were acquired at day 5 (c1), day 12 (c2), and day 25 (c3) following the DSS treatment are shown. d1–d3: The corresponding spin echo images are shown for the same colitis-bearing mouse as in (c1–c3). The normal colon in (a) and (b) is indicted by thin white arrows, while the inflamed colons in (c1–c3) and (d1–d3) are indicated by thicker white arrows.

FIG. 3

Contrast uptake curves for inflamed (colitis) colon, normal colon, and skeletal muscle. From DCEMRI studies, gadolinium uptake (in millimolar) as a function of time (in minutes) is shown for colitis (open circles), normal colon (open squares), and skeletal muscle (open triangle). Since the Gd uptake in normal colon and skeletal muscle overlaps, for visual clarity the scale of Gd enhancement for normal colon was multiplied by 2, indicated in the figure as “normal colon (×2).” Fits to the contrast uptake curves are shown for the TCM (Eq. 1, green line) and an EMM (Eq. 2, red line).

FIG. 4

Hematoxylin and eosin–stained histologic sections of colons from normal (a) and DSS-treated mice (b) prepared as Swiss rolls. Both images are displayed in the same scale, ×10. In the inflamed colon, white arrows indicate an area with healed epithelium and normal colon wall thickness. The yellow arrows indicate a colonic segment with complete ulceration. The mucosa is replaced by edematous granulation tissue and the colonic wall is markedly thickened.