A neurokinin-1 receptor antagonist that reduces intraabdominal adhesion formation increases peritoneal matrix metalloproteinase activity.
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.
Cohen
Philip A
PA
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Gower
Adam C
AC
Stucchi
Arthur F
AF
Leeman
Susan E
SE
Becker
James M
JM
Reed
Karen L
KL
D034841:Abdominal Cavity / Q000601:surgery; D000704:Analysis of Variance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D010537:Peritoneum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000267:Tissue Adhesions / Q000378:metabolism / Q000517:prevention & control*; D014945:Wound Healing / Q000187:drug effects*
C480026:6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D020782:Matrix Metalloproteinases