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Background: Ocular disease is known widely to occur in a subset of patients experiencing inflammatory bowel diseases. Although this extraintestinal manifestation has been recognized for a number of years, the pathogenetic mechanisms responsible for this distant organ inflammatory response are unknown., Methods: In the current study, we used a T-cell transfer model of chronic colitis in mice in which we quantified colonic inflammation, ocular function (electroretinography), ocular blood flow (intravital microscopy of the retina), intraocular pressure, and retinal hypoxia., Results: Ocular function in colitic mice was significantly impaired, with decreases in retinal b-wave amplitudes and oscillatory potentials. Moreover, retinal a waves and oscillatory potentials were delayed. Retinal blood flow was significantly reduced in the colitic mice, and this decrease in perfusion coupled with significant decreases in hematocrit would decrease oxygen delivery to the eye. Accordingly, mice with severe colitis showed increased levels of immunostaining for the hypoxia-dependent probe pimonidazole. Finally, intraocular pressures were found to be reduced in the colitic mice., Conclusions: Ocular disease occurs in a mouse model of chronic colitis, with retinal dysfunction seeming to be related to insufficient perfusion and oxygen delivery.

Background: Approximately one-half of patients with inflammatory bowel disease (IBD) suffer from anemia, with the most prevalent cause being iron deficiency. Accompanying the anemia are increases in erythropoietin, a plasma protein that can initiate the feedback production of new red blood cells. Anemia also occurs in animal models that are used to investigate the mechanisms of IBD; however, the extent to which iron deficiency produces the anemia in these animal models is unknown. Also unknown in the different animal models of IBD is whether the anemia upregulates the production of erythropoietin or, alternatively, whether a decrease in erythropoietin contributes to the induction of anemia., Methods: Two mouse models of colitis were used in this study: (1) acute 6-day ingestion of dextran sodium sulfate and (2) T-cell transfer into lymphopenic recipient mice. Measurements included indices of colitis severity, hematocrit, blood hemoglobin, plasma erythropoietin, serum iron concentration, plasma iron-binding capacities, transferrin saturation, and tissue iron concentrations., Results: Both models of colitis induced significant decreases in hematocrit, blood hemoglobin, and transferrin saturation, with the spleen and liver showing a decrease in iron content in the T-cell transfer model. Additionally, both models of colitis demonstrated significant increases in plasma erythropoietin and plasma iron-binding capacities., Conclusions: The measurements of iron, whether in acute (dextran sodium sulfate) or chronic (T-cell transfer) models of colitis, were generally consistent with iron-deficient anemia, with large increases in erythropoietin indicative of tissue hypoxia. These changes in animal models of colitis are similar to those found in human IBD.

Background: Hypoxia has been reported to be associated with the colonic inflammation observed in a chemically induced mouse model of self-limiting colitis, suggesting that low tissue oxygen tension may play a role in the pathophysiology of inflammatory tissue injury. However, no studies have been reported evaluating whether tissue hypoxia is associated with chronic gut inflammation. Therefore, the objective of the present study was to determine whether hypoxia is produced within the colon during the development of chronic gut inflammation., Methods: Adoptive transfer of CD4(+) T cells obtained from interleukin-10-deficient (IL-10(-/-)) mice into lymphopenic recombinase-activating gene-1-deficient (RAG(-/-)) mice induces chronic colonic inflammation, with the inflammation ranging from mild to severe as determined by blinded histological analyses. Colonic blood flow, hematocrit, and vascular density were determined using standard protocols, whereas tissue hypoxia was determined using the oxygen-dependent probe pimonidazole., Results: Adoptive transfer of IL-10(-/-) CD4(+) T cells into RAG(-/-) recipients induced chronic colonic inflammation that ranged from mild to severe at 8 weeks following T-cell transfer. The colitis was characterized by bowel wall thickening, goblet cell dropout, and inflammatory infiltrate. Surprisingly, we found that animals exhibiting mild colonic inflammation had increased hypoxia and decreased systemic hematocrit, whereas mice with severe colitis exhibited levels of hypoxia and hematocrit similar to healthy controls. In addition, we observed that the extent of hypoxia correlated inversely with hematocrit and vascular density., Conclusions: Changes in hematocrit, vascular density, and inflammatory state appear to influence the extent of tissue oxygenation in the T-cell-mediated model of chronic gut inflammation., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Background: Adoptive transfer of naive T-lymphocyte subsets into lymphopenic mice initiates chronic gut inflammation that mimics several aspects of inflammatory bowel disease (IBD). Patients with IBD can have profound alterations in intestinal blood flow, but whether the same is true in the T-cell transfer model has yet to be determined., Methods: In the current study, chronic intestinal inflammation was induced in recombinase-activating gene-1-deficient (RAG(-/-)) mice by adoptive transfer of CD4(+) T-lymphocytes obtained from interleukin-10 deficient (IL-10(-/-)) mice., Results: Four weeks later, widespread colonic inflammation was observed in the reconstituted recipients, in contrast to 2 control sets of mice injected with a different subset of lymphocytes or with vehicle alone. We observed that the resulting pathology induced in the reconstituted RAG(-/-) mice was divided distinctly into 2 subsets: 1 with blood flow near normal with very high inflammation scores, and the other with severely attenuated blood flow but with much lower signs of inflammation. Colonic and ileal blood flow rates in the latter subset of CD4(+) mice averaged only approximately 30% compared to the mice with higher inflammation scores. The lower blood flow rates were associated with greatly reduced red blood cell concentrations in the tissue, suggesting a possible loss of vascular density., Conclusions: In this model of chronic intestinal inflammation, mild inflammation was associated with significant decreases in blood flow.

Background: Ingestion by mice of dextran sodium sulfate (DSS) induces colonic vasoconstriction and inflammation, with some of the effects potentially mediated by the vasoconstrictor endothelin-1 (ET-1)., Methods: In this study, mice given 5% 40 kD DSS for 5-6 days had elevated colonic immunostaining for ET-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1). Increased ET-1 can induce microvascular constriction; however, the increase in PECAM-1 is consistent with angiogenesis that could decrease flow resistance., Results: Our measurements of intestinal blood flow, via infused microspheres, suggests that these 2 factors may offset each other, with only a nonsignificant tendency for a DSS-induced decrease in flow. Daily administration of the endothelin converting enzyme inhibitor SM-19712 (15 mg/kg) attenuated DSS-induced increases in colonic immunostaining of ET-1 and PECAM-1., Conclusions: SM-19712 attenuated histologic signs of tissue injury and inflammation induced by DSS, and decreased the extent of loose stools and fecal blood. However, the inhibitor did not significantly decrease DSS-induced colon shortening or tissue levels of myeloperoxidase (an indicator of neutrophil infiltration).