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A neurokinin‐1 receptor antagonist that reduces intraabdominal adhesion formation increases peritoneal matrix metalloproteinase activity
Author(s) -
Cohen Philip A.,
Gower Adam C.,
Stucchi Arthur F.,
Leeman Susan E.,
Becker James M.,
Reed Karen L.
Publication year - 2007
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1524-475x.2007.00291.x
Subject(s) - matrix metalloproteinase , extracellular matrix , adhesion , antagonist , tachykinin receptor 1 , medicine , receptor antagonist , peritoneum , receptor , tissue inhibitor of metalloproteinase , peritoneal fluid , pharmacology , chemistry , substance p , pathology , neuropeptide , biochemistry , organic chemistry
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 <0.05) at 7 days and significantly increased the total MMP activity in peritoneal fluid at 24 hours. There was an accompanying increase ( p <0.05) in MMP‐8 and MMP‐9 mRNA expression and activity in peritoneal tissue and fluid, respectively. MMP‐3 mRNA was also increased in the 24‐hour peritoneal tissue, and exposure of Met‐5A cells to SP reduced MMP‐3 expression and activity. These data support a role for MMPs, specifically MMP‐3, MMP‐8, and MMP‐9, in intraabdominal adhesion formation and suggest that the NK‐1R antagonist may reduce adhesions, in part, by increasing MMP activity in the peritoneum by 24 hours after surgery.