Dysfonctionnements radioinduits du transport colique : rôle du système nerveux entérique et de la serotonine
Agnès François, Thèse de doctorat Paris VI, 3/12/98
Introduction : One of the most commonly observed features of radiation-induced injury of the gastrointestinal tract is the appearence of severe diarrhea. One difficulty in understanding the origin of radiation-induced diarrhea is the multiplicity of factors implicated, depending on the type of radiation, the dose received and the irradiated dield. Colonic transport is regulated for a great part by the enteric nervous system. (ENS), in close association with immunocompetent cells, especially mast cells. Purpose : The aim of this study was to investigate wether the neuroimmune regulation of colonic transport could be implicated in radiation-induced attenuation and recovery of colonic functions. Methods and results : Male Wistar rats were whole-body irradiated at 3.8 Gy neutron or 5 and 10 Gy gamma. At 1 and 3 days after exposure, the colonic epithelium was hyporesponsive to neural stimulation (submucosal plexus). Mechanistic studies were performed after 10 Gy exposure. The decreased colonic transport was associated with the disappearence of both submucosal mast cells and histamine-mediated pathway, together with decreased responses to exogenous histamine. Similary, the response to exogenous 5-HT was decreased, without any modification of either the neural (5-HT3) or non-neural (5-HT4) pathways. Seven days after exposure, colonic transport capacity returned to normal in spite of the absence of mast cells. However these observations were associated with the reappearence of a histaminergic pathway, the origin of which is still unknown. The part played by 5-HT3 receptors was increased, together with the appearence of a neurally-associated 5-HT4 receptor-pathway. Conclusion : These results suggest that the decreased influence of the ENS on colonic transport observed 1 and 3 days after exposure may be due to both the disappearence of neuroimmune links and the hyporesponsiveness of colonic epithelium to the mediators released by ENS. The functional recovery at seven days may be related on one hand to the return of altered properties but also on the other hand by the establishment of substitute neural pathways : an histaminergic pathway and a serotoninergic pathway, with probably a combined action of both 5-HT3 and 5-HT4 receptors. Whereas colonic transport dysfunction seems to be mostly related to the epithelium, the ENS may play a role in the restablishment processes of colonic functions after radiation exposure.