gms | German Medical Science

Introduction: Localized abdominal surgery frequently leads to postoperative ileus (POI) of the entire intestinal tract, causing prolonged morbidity. Intestinal macrophages are known to produce mediators that paralyze myocytes, but it is unclear how macrophages are activated, especially those in non-manipulated intestinal areas. Our model of intestinal manipulation (IM) in rodents describe the pathomechanisms of a local surgical trauma of the jejunum and its propagation to unmanipulated gastrointestinal segments, the so called field effect. Our study should clarify what the jejunal macrophages activates and which pathomechanisms contribute to the gastrointestinal field effect.

Materials and methods: Jejunal and colonic muscularis of C57Bl/6 mice (WT) and of different immunological knockout mice (such as CD4-/-, INF-γ-/-, Tbet-/-, DEREG, Il-12-/-) on C57Bl/6-background were isolated after IM and sham-operation. Dendritic cells and CD4+ T cells were separately isolated from submucosa, muscularis and portal vein blood and analyzed by FACS and proliferation assays. The activation patterns of immunological mediators were determined by PCR. The pharmacological blockage of T cells was performed by i.p. administration of FTY-720. The gut motility was determined by measurement of gastrointestinal and colonic transit time in vivo and by measurement of muscularis contractility in vitro by setups.

Results: Our results demonstrate that intestinal surgery activates intestinal CD103⁺ CD11b⁺ dendritic cells to produce IL-12 that stimulates CCR9⁺ memory T helper type 1 (Th1) cells to produce IFN-g, which activates the macrophages. IL-12 also caused some Th1 cells to migrate from surgically manipulated sites through the bloodstream and lymphatic stream to unmanipulated intestinal areas to induce POI there. Preventing T cell migration by the drug FTY720, or inhibition of IL-12, T-bet or IFN-g prevented POI. CCR9⁺ Th1 memory cells were detected also in the peripheral venous blood of humans one hour after abdominal surgery, but not in humans after extraabdominal surgery.

Conclusion: These findings demonstrate that POI is a Th1 immune-mediated disease and identify potential targets for disease monitoring and possible therapy.