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Lack of Anti-Inflammatory Mediators in Ulcerative Colitis: A Possible New Mechanism
Martin Mangino, Lionel Brounts, Bruce Harms, Charles Heise, University of Wisconsin, Madison, WI
Inflammatory bowel disease (IBD) is characterized by persistent chronic inflammation of the bowel wall. Although the disease is currently treated with anti-inflammatory medications, the underlying mechanisms of the disease are poorly understood. Lipoxins are novel lipid mediators derived from arachidonic acid that possess powerful anti-inflammatory effects on neutrophil function. These messengers are produced late in an inflammatory response and their presence serves to resolve inflammation. Since these mediators are produced in intestinal mucosa, we hypothesized that IBD may be caused, in part, by a failure to resolve inflammation by a defect in lipoxin synthesis or metabolism. Seemingly innocuous inflammatory stimuli, such as gut bacteria or food antigens, may result in runaway inflammation without anti-inflammatory mediators to resolve the initiated response.
Methods: To test this hypothesis, we measured mucosal lipoxin synthesis in surgically resected colonic specimens from patients with ulcerative colitis (UC) and compared these levels to a normal control group (organ donors). Results:In vitro Lipoxin A4 synthesis was significantly less (24 fold) in colon specimens from UC patients (n=15), relative to the organ donor controls (n=5). This effect was not attributable to steroid therapy, which can interfere with lipoxin synthesis, since a sub-group of UC patients without steroid treatment also produced significantly less lipoxins. Aspirin treated tissue (in-vitro) from UC patients produced aspirin triggered lipoxins (ATL), which are biologically active isomers of native lipoxins produced by aspirin treated COX-2. Thus, although UC colonic mucosa was not able to generate native lipoxins, the cells could be coaxed to produce artificial lipoxin isomers with aspirin treatment. In other experiments, a 15-lipoxygenase iso-enzymes sufficient for native lipoxin synthesis was deficient in UC patients, relative to normal colon. Conclusions:We conclude that patients with ulcerative colitis have a limited capacity to synthesize anti-inflammatory lipid mediators. This may be a causal factor in the chronic inflammation characteristics of UC and may represent the foundation of future treatment efforts.
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