Ropivacaine and cellular functions : Towards an understanding of efficacy in ulcerative colitis

Sammanfattning: Ulcerative colitis is an inflammatory condition affecting the mucosa of the colon and the disease is characterised by periods of active colonic inflammation, intermitted by periods of remission. Local anaesthetics have been shown to exhibit a wide array of anti inflammatory effects in addition to the reversible block of nerve impulse propagation, and some or maybe all of these may explain the reported beneficial effects of local anaesthetics in ulcerative colitis patients. This thesis is focused on the effects of ropivacaine, a new local anesthetic, on a number of cellular functions with special reference to its use as a potential new therapy in ulcerative colitis. Local ropivacaine therapy in experimental TNBS-induced colitis in rat reduced the morphological damage and myeloperoxidase activity (reflecting neutrophil recruitment). The migration of leukocytes into tissues is a crucial event in the inflammatory response and contributes to the pathology of ulcerative colitis. Ropivacaine was found to inhibit inflammatory leukocyte adhesion, possibly through reduced leukocyte expression of CDllb/CD18 and reduced rolling leukocyte flux. The increased plasma exudation associated with inflammation was also reduced, presumably as a result of ropivacaine's effects on leukocyte-endothelial interactions. Prostaglandins and leukotrienes have been found at high concentration in ulcerative colitis and have been suggested to be involved in the inflammatory response. Ropivacaine reduced the release of the pro-inflammatory lipoxygenase products LTB, and 5-HETE in a stimulus-specific manner without influencing the biosynthesis of potentially cytoprotective eicosanoids such as 15-HETE and prostacyclin. Inflammation of the gastrointestinal tract results in disturbance of motility, such as colonic hypomotility and unresponsiveness to contractile stimuli, which contributes to commonly observed clinical features, such as diarrhea. Ropivacaine acutely restored the contractile response to acetylcholine in experimental colitis. The effect was apparent after a short incubation period, indicating a direct effect on tissue contractility in response to acetylcholine which may contribute to prompt symptomatic relief. Resident structural cells, such as fibroblasts, endothelial cells and epithelial cells, may act as active contributors to the regulation of the inflammatory response since these cells are hyperpoliferative during the inflammatory reaction and produce many of the signalling molecules, such as cytokines, that contribute to inflammation. Ropivacaine inhibited serum-induced proliferation of all three human cell types in vitro. The control of cell number per se by ropivacaine implies an indirect control of the release of inflammatory mediators. Moreover, the frequency of colon cancer is enhanced in ulcerative colitis and ropivacaine was found to inhibit the proliferation of colon cancer cells in vitro in a dose-dependent manner, suggesting that ropivacaine treatment will not contribute to the increased cancer incidence. In summary, the data presented in this thesis indicate that ropivacaine may be a valuable new treatment for ulcerative colitis. Doctoral Thesis ©Titti Martinsson