4.5 Article

Iatrogenic extracellular matrix disruption as a local trigger for postoperative ileus

Journal

JOURNAL OF SURGICAL RESEARCH
Volume 178, Issue 2, Pages 632-639

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jss.2012.05.044

Keywords

Extracellular matrix; Hyaluronan; Postoperative ileus; CD44; TIMP-1; MMP-9

Categories

Funding

  1. National Institutes of Health [R01-GM58241, R01-DK068610, P50-GM-53789, DK02488]
  2. BONFOR program of the Bonn University Medical Faculty
  3. BONFOR grant [0-112.0032]

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Background: Active matrix metallopeptidase 9 (MMP-9) disruption of the extracellular matrix (ECM) plays an important role in inflammatory disorders. In this study, we investigated the inflammatory role of MMP-9 and the ECM breakdown product hyaluronan as a trigger for the postoperative intestinal inflammatory response of postoperative ileus. Methods: We performed a standardized intestinal surgical manipulation on rats to produce ileus assessed by the oral non-digestible fluorescein isothiocyanate-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 metalloproteinase 1 levels by enzyme-linked immunosorbent assay (ELISA). We cultured peritoneal macrophages and exposed them to peritoneal fluid or synthetic hyaluronan for ELISA analysis of IL-6 and macrophage inflammatory protein-1 alpha. Results: 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-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-1 alpha in the macrophage supernatant. Conclusions: Our results confirm that MMP-9 disruption in the ECM with hyaluronan release and muscularis CD44 receptor induction has the potential to trigger muscularis proinflammatory cascades that cause postoperative ileus. Matrix metallopeptidase 9 inhibition may be a novel therapeutic approach to limit postoperative ileus. (C) 2012 Elsevier Inc. All rights reserved.

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