Die orale Gabe von CPSI 2364 verhindert den postoperativen Ileus im Großtiermodell ohne Beeinflussung der intestinalen Wundheilung Oral CPSI 2364 prevents postoperative ileus in swine without impairment of intestinal wound repair

Background. The mechanical trauma of the gut is an unavoidable consequence of abdominal surgery leading to postoperative ileus (POI). Former studies revealed that activation of resident macrophages in the muscularis externa (ME) is an initial step in the inflammatory cascade resulting in massive inflammation of the bowel wall with intestinal dysmotility [1, 2]. The aim of this study was to investigate the efficacy of the macrophage-specific c-Raf-pathway inhibitor CPSI 2364 in preventing POI in swine. Additionally, we investigated disturbances of intestinal wound repair, as macrophage-function is essential in this process [3]. Materials and Methods. Swine were treated orally with placebo or 1mg/kg CPSI 2364 before standardized intestinal manipulation. 24 h later swine were sacrificed and the whole digestive tract was removed for further investigation. Inflammation within the ME of the small bowel was quantified using RT-PCR (MCP-1) and a myeloperoxidase-assay. To examine smooth muscle function, jejunal muscularis strips were exposed to an increasing concentration of a muscarinic agonist in an in vitro organ bath and contractility was analyzed. Furthermore intestinal transit time was measured in vivo. In a second experiment swine received an anastomosis of the colon to examine intestinal wound repair. On postoperative day 6 mRNA levels of wound healing parameters (VEGF, Collagen 1 and 3) and perianastomotic hydroxyproline concentration were examined. To assess mechanical strength bursting pressure was measured. Results. After treatment with CPSI 2364 a significant inflammatory reduction within the ME on mRNA- and cell-level could be demonstrated. Furthermore, smooth muscle function was improved, resulting in an accelerated intestinal transit time and an elevated contractility. Clinical course and perianastomotic mRNA-levels, hydroxyproline concentration or bursting pressure showed no evidence of impaired intestinal wound healing. Conclusion. Preoperative application of CPSI 2364 reduces postoperative inflammation within the ME subsequently preventing POI. A detrimental influence of CPSI 2364 on intestinal wound repair could not be demonstrated.