The role of inflammatory mediator cells in the pathogenesis of colitis in experimental animal models

The underlying feature of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, is the influx of inflammatory cells. These cells include neutrophils and lymphocytes, which have been implicated in tissue damage. These studies investigated the role of neutrophils and T-lymphocytes in colitis. Acute colitis was induced by giving mice 4% DSS in their drinking water. First, Interleukin-8 (a potent chemoattractant) was given to mice with DSS-induced colitis to increase the influx of neutrophils. In a separate study, mice were given DSS-induced colitis with a CXCR2 (neutrophil chemoattractant receptor) antagonist (S13265610) to decrease neutrophil influx. The immune complex model of rabbit colitis was also used for the CXCR2 studies because this model produces a primarily neutrophil driven disease. Second, SCID and RAG2 (T and B-cell deficient) mice on a Balb/c and 129SvEv background were given DSS-induced colitis. In addition, SCID mice were adoptively transferred with a pro-inflammatory subset of T-cells (CD45RBhigh cells) and then given DSS-induced colitis 2 or 4 weeks later. Results of these studies showed that IL-8 caused a significant increase in disease severity. Administration of the CXCR2 antagonist led to a significant decrease in disease severity in both mice and rabbits. SCID and RAG2 mice had significantly less disease than their immune-intact controls. RAG2 mice on a 129SvEv background had significantly less disease than RAG2 on a Balb/c background even though there was no difference between the Balb/c and 129SvEv control mice. RAG2 mice had significantly less disease than SCID mice. SCID mice that were adoptively transferred with CD45RBhigh T-cells and given DSS-induced colitis 4 weeks later, demonstrated a higher disease than the other groups. It can be concluded that neutrophils and T-lymphocytes play an essential role in the pathogenesis of colitis in the experimental animal models utilized here. CD45RBhigh T-cells exhibit their pro-inflammatory effect in the DSS model. In addition, this study demonstrates a difference in genetic susceptibility to DSS-induced colitis. Finally, this work represents a significant finding of a therapeutic potential use of CXCR2 antagonists in the treatment of human IBD.