Fatal acute intestinal pseudoobstruction in mice

Abstract

Here we describe the epizootiology and pathology of spontaneous, fatal acute intestinal pseudoobstruction that occurred in a mouse colony of 1000 breeding pairs, mainly of the C57Bl/6 strain and free from known pathogenic agents. Most of the mice affected were dams in the second week of lactation. At necropsy, segments of the small intestines were distended with fluid contents. Widespread apoptosis of the villus epithelium of the small intestine and superficial epithelial cells of the large intestine, associated with strong expression of active caspase 3, was a distinctive feature. Necrotic enterocytes, mucosal erosions, and acute mucosal inflammation were prominent in some mice, and morphologic signs of toxemia were generally present. No light microscopic neuronal changes were apparent in the gut, and no etiologic agents were identified. These results indicate that sudden activation of apoptosis in the trophically stimulated gut epithelium during peak lactation was instrumental for the fatal outcome of the condition, but the primary cause of the motility dysfunction of the bowel was not established.

Figure 1.

Day of death relative to day of lactation in lactating mice with signs of intestinal pseudoobstruction (n = 99).

Figure 2.

Skinned mouse with IPO. Markedly enlarged intestinal loops are visible through the unincised abdominal wall.

Figure 3.

Gastrointestinal tract of mouse with IPO. Segmentally dilated small intestine, most severely proximally. Note abrupt ending of dilation, fluid and frothy contents, pellets of dry ingesta, and empty colon. Moderate dilation of stomach and cecum also is apparent.

Figure 4.

Histology of jejunum in (A) control mouse and (B through D) mice with IPO. (A) Regularly shaped villi lined by intact, moderately crowded columnar epithelium. (B) High numbers of detached acidophilic cells with pyknotic nuclei in the gut lumen between villi. (C) Eroded mucosa. Inflammatory cell infiltrate in the mucosa and submucosa. (D) Transversally cut mucosal crypts with luminal necrotic leukocytes and cellular debris. Hematoxylin and eosin stain; Bar, 100 μm (A through C), 50 μm (D).

Figure 5.

Immunostaining for active caspase 3, predominantly in the gut epithelium at the top of villi and in cells detached in the gut lumen. Stained by using a monoclonal antibody to active caspase 3 and conjugation with peroxidase, and visualized by using EnVision (Dako). Bar, 100 μm.

Figure 6.

Transmission electron microscopy of upper jejunum from mouse with IPO. A. Apoptotic epithelial cell disintegrating in the gut lumen. Nucleus (N) with marginated, condensed chromatin. Densely packed organelles, including mitochondria and electron-dense vesicles, are visible. Superficial parts of intact surface epithelial cells are visible at left (*). Original magnification × 5600. (B) Parts of villus enterocytes. Apoptotic body (arrow) with condensed nuclear chromatin and densely packed organelles. The nucleus of an enterocyte is indicated (N). Original magnification × 1950.