The inflammatory bowel diseases (Crohn's disease, ulcerative colitis; IBD) are chronic idiopathic inflammatory disorders of the intestinal tract. IBD is characterized by the infiltration of large numbers of monocytes, lymphocytes, and neutrophils into the intestinal interstitium accompanied by extensive mucosal and/or transmural injury. Recent evidence suggests that interaction between collagen-binding integrins (e.g. alpha-1-beta-1) and the extracellular matrix promotes the migration and/or activation of leukocytes in different models of inflammation. However, relatively little information is available describing the importance of leukocyte-interstitial matrix interactions in chronic gut inflammation. Therefore, the overall objective of this study is to better understand the role of the alpha-1-beta-1 collagen-binding integrin in the pathophysiology of chronic gut inflammation in an immune-based murine model of chronic colitis. Hypothesis: We propose that T-cell and/or granulocyte-associated integrin alpha-1-beta-1 interacts with interstitial collagen in the colonic interstitium resulting in the activation of these cells with the upregulation of certain proinflammatory cytokines that may initiate and/or perpetuate chronic gut inflammation. In order to test this hypothesis we propose the following specific aims: 1) Evaluate the importance of T-lymphocyte alpha-1-beta-1 surface expression on the promotion of chronic gut inflammation using donor T-cells from alpha-1-deficient (alpha1-/-) mice. 2) Determine the importance of granulocyte (e.g. monocyte/macrophage, PMNs) alpha-1-beta-1 surface expression on the initiation and/or perpetuation of chronic gut inflammation using RAG-2-/- x alpha-1-/- double-deficient recipient animals. Understanding the importance of this integrin in an immune-based model of IBD may provide new insights into the pathogenesis of chronic gut inflammation and provide new therapeutic approaches for the treatment of human IBD.
