S1776 Chronic Lung and Liver Inflammation in a Mouse Model of Crohn's Colitis

Abstract

Recent population-based studies demonstrate that in addition to the more common joint and hepatobiliary extraintestinal manifestations observed in patients with one of the inflammatory bowel diseases (IBD), pulmonary inflammation is a very common comorbidity increased in Crohn's disease. Because few studies have reported the presence of extraintestinal inflammation in mouse models of IBD, we undertook a systematic histopathological study to document the presence (or absence) of lung and liver inflammation in a mouse model of CD. Chronic colitis was induced in RAG-1-deficient (RAG-/-) mice by the adoptive transfer of naive (CD4+CD45RBhigh) T-cells (5x105 cells per mouse) obtained from the spleens of healthy donor mice. PBS-injected RAG-/mice were used as controls. Colons, lungs and liver as well as heart, kidneys, and brain were excised, fixed in formalin, embedded, sectioned and stained with H&E. Blinded histopathological analysis was performed on each organ by a pathologist not familiar with the experimental groups. We found that at 6-8 weeks post Tcell transfer, the majority of T-cell injected mice (80%) became moribund and were euthanized whereas PBS-injected animals appeared healthy throughout the entire 8week observation period. Blinded histopathological examination of the colons obtained from RAG-/mice injected with naive T-cells revealed moderate-to-severe colitis characterized by dramatic transmural T-cell and PMN infiltration, bowel wall thickening, Goblet cell dropout and epithelial cell erosions. Intracellular cytokine analysis of T-cells obtained from the colon and MLNs of colitic mice showed enhanced production of both IFNγ and IL-17. Surprisingly, we found that virtually all mice injected with naive T-cells presented with chronic bronchitis/ pulmonary inflammation. In many cases (>60%) confluent inflammation merged together between small and medium sized bronchi. Varying degrees of perivascular lymphocytic cuffing were also observed in virtually all of the mice however few PMNs were observed and vasculitis was absent. Lung parenchyma involvement was mild and patchy. In addition to gut and lung inflammation, we also observed significant hepatocellular necrosis with periportal and lobular lymphocytic inflammation. There was no evidence of bile ductal damage. No significant inflammation was observed in the heart, kidneys or brain of the colitic animals and no inflammation was observed in any organ system of the PBS controls. Taken together, these data demonstrate, for the first time, that pulmonary and liver inflammation is a occurrence in the T-cell transfer model of chronic colitis (Supported by NIH PO1 43785).