Die Fragmentierung der Extrazellulären Matrix als lokaler Trigger für den postoperativen Ileus

Abstract

<strong>Iatrogenic extracellular matrix disruption as a local trigger for postoperative ileus</strong><br /><em>Background:</em> Active matrix metallopeptidase 9 (MMP-9) disruption of the extracellular matrix (ECM) plays an important role in inflammatory disorders. In this study, we inves- tigated the inflammatory role of MMP-9 and the ECM breakdown product hyaluronan as a trigger for the postoperative intestinal inflammatory response of postoperative ileus. <br /><em> Methods:</em> We performed a standardized intestinal surgical manipulation on rats to produce ileus assessed by the oral non-digestible fluorescein isothiocyanate e dextran transit assay. We studied isolated intestinal muscularis extracts for mRNA expressions of interleukin 6 (IL-6), MMP-9 and CD44. We quantified peritoneal MMP-9 activity using zymography, and quantified peritoneal fluid and serum for hyaluronan and tissue inhibitor of metal- loproteinase 1 levels by enzyme-linked immunosorbent assay (ELISA). We cultured peri- toneal macrophages and exposed them to peritoneal fluid or synthetic hyaluronan for ELISA analysis of IL-6 and macrophage inflammatory protein-1α .<br /><em>Results:</em> Transit was significantly delayed after surgical manipulation, and extracts of the isolated jejunal and colonic muscularis demonstrated a significant induction of IL-6, MMP- 9, and CD44 mRNAs compared with controls. Zymography confirmed significant MMP-9 activity in peritoneal fluid compared with controls. Enzyme-linked immunosorbent assay measurements showed a significant up-regulation in hyaluronan and tissue inhibitor of metalloproteinase 1 in the peritoneal fluid and serum. In addition, ELISA and reverse transcriptase e polymerase chain reaction measurements of peritoneal macrophages stimulated with postsurgical peritoneal fluid and synthetic hyaluronan resulted in higher expressions of IL-6 and macrophage inflammatory protein-1α in the macrophage supernatant.<br /><em>Conclusions</em>: Our results confirm that MMP-9 disruption in the ECM with hyaluronan release and muscularis CD44 receptor induction has the potential to trigger muscularis proin- flammatory cascades that cause postoperative ileus. Matrix metallopeptidase 9 inhibition may be a novel therapeutic approach to limit postoperative ileus.