An investigation into the defective termination and resolution of acute inflammation in ulcerative colitis (360G-Wellcome-100098_Z_12_Z)

Ulcerative colitis (UC) is a chronic inflammatory disorder, associated with protracted acute inflammation after bacterial challenge. I postulate that this results from failure of the mechanisms that normally terminate inflammation. The skin window technique permits examination of acute inflammatory responses in vivo following tissue damage or applied immunomodulators. I will use this to investigate the cellular, soluble inflammatory mediator and gene transcription responses in UC patients, h ealthy individuals and inflammatory disease controls, over a long time course to evaluate the switch from acute inflammation to defervescence and tissue repair. This will identify where UC responses diverge, and indicate whether pro-inflammatory pathways are appropriately discontinued and pro-resolution mediators engaged. The relevance of this model will be confirmed in the bowel using a serial biopsy technique. I will then attempt to define the regulatory mechanisms responsible by examining specific processes in vitro, guided by results from the in vivo models. These experiments will be performed on cultured leukocytes (derived from peripheral blood and intestinal specimens), fibroblasts and other cells identified as relevant in the skin windows. Finally, I will explore the mechanisms and consequences of previously identified disturbances in UC macrophage Toll-like receptor signalling, likely to impact on orchestration of inflammatory responses.