The neurokinin 1 receptor regulates peritoneal fibrinolytic activity and postoperative adhesion formation.
BACKGROUND
Intra-abdominal adhesions are a common source of postoperative morbidity. Previous studies in our laboratory have shown that a neurokinin 1 receptor antagonist (NK-1RA) reduces abdominal adhesion formation and increases peritoneal fibrinolytic activity. However, the cellular pathway by which the antagonist exerts its effects is unclear, as cultured peritoneal mesothelial cells exposed to the NK-1RA show increases in fibrinolytic activity despite having very low expression of neurokinin 1 receptor (NK-1R) messenger RNA and protein. Our aim was to determine whether the NK-1R plays an essential role in the adhesion-reducing effects of the NK-1RA, or if the NK-1RA is acting independently of the receptor.


METHODS
Homozygous NK-1R knockout mice and age matched wild-type mice underwent laparotomy with cecal cautery to induce adhesions. At the time of surgery, mice received a single intraperitoneal dose of either NK-1RA (25 mg/kg) or saline alone. Adhesion severity at the site of cecal cautery was assessed on postoperative day 7. In a separate experiment, peritoneal fluid was collected from wild type and NK-1R knockout mice 24 h after laparotomy with cecal cautery and administration of either NK-1RA or saline. Tissue plasminogen activator levels, representative of total fibrinolytic activity, were then measured in peritoneal fluid.


RESULTS
In wild-type mice, NK-1RA administration significantly decreased adhesion formation compared with saline controls. Among the NK-1R knockout mice, there was no significant reduction in adhesion formation by the NK-1RA. Fibrinolytic activity increased 244% in wild-type mice administered NK-1RA compared with saline controls; however, the NK-1RA did not raise fibrinolytic activity above saline controls in NK-1R knockout mice.


CONCLUSIONS
These data indicate that the NK-1R mediates the adhesion-reducing effects of the NK-1RA, in part, by the upregulation of peritoneal fibrinolysis, and suggest that the NK-1R is a promising therapeutic target for adhesion prevention.
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Michael R
MR
Cassidy
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Holly K
HK
Sheldon
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Melanie L
ML
Gainsbury
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Earl
E
Gillespie
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Hisashi
H
Kosaka
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Stanley
S
Heydrick
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts. Electronic address: astucchi@bu.edu.
Arthur F
AF
Stucchi
D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002432:Cecum / Q000293:injuries / Q000601:surgery; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007813:Laparotomy / Q000009:adverse effects; D008297:Male; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D010537:Peritoneum / Q000378:metabolism* / Q000473:pathology; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D000267:Tissue Adhesions / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000378:metabolism
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; D013373:Substance P; D010959:Tissue Plasminogen Activator
Fibrinolytic activity; Intra-abdominal adhesions; Neurokinin-1 receptor; Neurokinin-1 receptor antagonist; Substance P; Tissue plasminogen activator