A neurokinin-1 receptor antagonist that reduces intraabdominal adhesion formation increases peritoneal matrix metalloproteinase activity

ABSTRACT Adhesions remain a significant complication of abdominal surgery. There is a growing body of evidence suggesting that remodeling of peritoneal extracellular matrix by matrix metalloproteinases (MMPs) is involved in adhesion formation. We have shown that administration of a specific neurokinin‐1 receptor (NK‐1R) antagonist (CJ‐12,255, Pfizer) to rats within 5 hours of surgery reduces intraabdominal adhesion formation. Because substance P (SP), the primary NK‐1R ligand, is known to augment tissue fibrosis, the aim of this study was to determine the effects of NK‐1R antagonist administration on peritoneal MMP expression and activity 24 hours after surgery in a rat adhesion model. Following laparotomy, four ischemic buttons were created on the peritoneum of rats that received either an intraperitoneal NK‐1R antagonist or a vehicle at surgery. Adhesion formation was assessed 7 days later. Peritoneal fluid and tissue were collected at 24 hours to assess total MMP activity, as well as MMP‐2, MMP‐8, and MMP‐9 activity. Specific MMP and tissue inhibitors of MMP mRNAs were measured, and the effects of SP on MMP‐3 expression were determined in Met‐5A cells, a human peritoneal mesothelial cell line. NK‐1R antagonist administration reduced adhesion formation by 47% (p