Depletion und Inaktivierung intestinaler Muskularis-Makrophagen verhindern den postoperativen Ileus

Abstract

Background and aims: Abdominal surgery results in a massive inflammatory reaction within the intestinal wall leading to postoperative ileus. Results of previous investigations suggested that resident macrophages within the intestinal muscularis play an important role in the local inflammatory process. Aim of this study was to determine if depletion and inactivation of these macrophages would lead to a reduction of the local inflammation and subsequently to a normalization of smooth muscle function. Methods: Sprague-Dawley rats underwent a standardized model of intestinal manipulation. Depletion and inactivation-groups were pretreated i.v. with clodronate-encapsulated-liposomes and gadolinium chloride. Cytokine mRNA expression (IL-Iβ, IL-6, TNF-α) was determined by real-time RT-PCR in isolated bowel wall layers. Muscularis whole mounts were used for histo- and immunohistochemistry to quantify leukocyte populations. Gastrointestinal transit was measured in-vivo after ingestion of fluorescently labelled dextran. In-vitro muscle contractility was measured in a standard organ bath using jejunal muscle strips. Statistical analysis was done with the student t-test and ANOVA, p < 0.05. Results: Pretreatment resulted in 85% depletion of muscularis macrophages. Cytokine mRNA levels showed a maximum increase at 3 hours after manipulation. Pretreament significantly reduced the induction within the muscularis. Intestinal manipulation led to a massive infiltration into the muscularis, which was decreased significantly by pretreatment. The inflammatory reaction was followed by a significant decline in muscle contractility in untreated animals, but not significantly altered after pretreament. This functional improvement could also be demonstrated by analysis of gastrointestinal transit. Conclusions: These data show that depletion and inactivation of resident muscularis macrophages decrease the local inflammatory response and smooth muscle dysfunction following surgical intestinal trauma. Therefore, this study shows for the first time that resident macrophages of the intestinal muscularis are causally involved in the local inflammatory reaction and subsequent functional impairment of the smooth muscle, which leads to postoperative ileus.