Fig 1.
Histology of colitis in TIA mice.
TIA mice generally presented with moderate to severe pan-colitis, primarily involving the mucosa, as shown in these representative fields derived from the terminal colon/rectum (A), distal colon (B), and mid-colon (C). The lamina propria is packed with inflammatory cells. Representative crypt abscesses are indicated by arrows. “e” in panel B denotes areas of edema in the submucosa. Scale bar represents 500 μm in A and 250 μm in B and C.
Fig 2.
Squamous metaplasia and neoplasia in TIA mice.
A. Squamous metaplasia (arrowheads) was common in the rectum of TIA mice, shown here in a 9 week old. B. The dotted lines highlight a focus of invasive mucinous adenocarcinoma identified in the proximal colon of a 15 week old TIA mouse with severe pan-colitis (histologic score = 55). “Mu” indicates mucin lakes associated with invasive carcinoma. Scale bar in A and B represents 500 μm.
Table 1.
Serum cytokine and chemokine levels in T/I, TIA, and control T/Ihet micea.
Fig 3.
Serum immunoglobulin concentrations in TIA, T/I, and control T/Ihet mice.
The serum concentration of various immunoglobulin isotypes are shown for 8–10 week old TIA (n = 17), T/I (n = 28), and control T/Ihet mice (n = 13). Values shown represent the mean ± standard error of the mean (SEM). Values obtained for TIA mice were statistically different than for T/I mice for all isotypes tested, with p values ranging from p = 0.006 for IgM to 7 x 10−12 for IgG3 (Student’s t-test).
Fig 4.
Survival of T/I and TIA mice as a function of age.
To prevent unnecessary suffering, morbidity that triggered humane endpoints was used as a surrogate for mortality, as described in Materials and Methods. Kaplan-Meier analysis demonstrates that TIA mice have a significantly shorter mean survival (13 weeks) than T/I mice (21 weeks; p = 0.0001, log-rank test).
Fig 5.
Incidence and multiplicity of colonic neoplasia in T/I versus TIA mice.
A. The number of tumors per mouse is shown for T/I (n = 19) and TIA mice (n = 41). Each point represents a single mouse. The p value shown is the result of a multivariable analysis that adjusted for age when neoplasia was ascertained (Poisson regression analysis). B. The number of tumors per mouse is shown as a function of age at euthanasia for the same cohort illustrated in panel A. Each point represents a single mouse, however some points are not visible due to multiple mice with the same age and tumor count.
Fig 6.
Colonic metaplasia of Brunner’s glands and duodenal inflammation in TIA mice.
A. The pyloric region of the glandular stomach (left of dashed line) and the duodenum (right of dashed line) are shown. The duodenal mucosa demonstrates mucosal epithelium and Brunner’s glands with loss of villous architecture and histology similar to that seen in the colon (colonic metaplasia). B. A higher magnification views demonstrates the metaplastic epithelium and surrounding lamina propria and submucosa with marked chronic and active inflammation, similar to what was observed in the colon of these mice. Images shown are from a 9 week mouse, where some residual cells (arrows) exhibit morphology typical of Brunner’s glands. Older mice with such metaplasia typically lacked residual identifiable Brunner’s glands. Scale bar represents 500 μm in A and 50 μm in B.
Fig 7.
Stomach inflammation in TIA mice.
The dashed line in A represents the boundary between the forestomach and the glandular stomach. A higher magnification view in B shows inflamed gastric glands that resemble crypt abscesses, with thinning of glandular epithelium and neutrophils present within the dilated lumens, as indicated by arrows. Scale bar represents 500 μm in A and 50 μm in B.