title: N-acetyl-l-cysteine decreases intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses.
abstract: BACKGROUND
  Intraperitoneal adhesions occur in more than 94% of patients after abdominal surgery. Mechanisms that decrease oxidative stress and upregulate peritoneal fibrinolysis reduce adhesions. N-acetyl-l-cysteine (NAC) is a clinically relevant antioxidant whose effect on peritoneal fibrinolysis and ability to decrease adhesions has not been established. The aims of this study were to determine if NAC reduces adhesions and to characterize its potential mechanism(s) of action.
  
  
  METHODS
  Male Wistar rats (n = 92) received 0.9% saline (OP Control), intraperitoneal NAC (150 mg/kg, OP + NAC), or oral NAC (1200 mg/kg) twice daily on preoperative day 1, day of operation, and postoperative day 1. Adhesions were induced on the day of operation using our previously described ischemic button model. Animals were killed on postoperative day 7 for adhesion scoring. Peritoneal tissue and fluid from the intraperitoneal NAC group were measured at 24 hours for fibrinolytic activity, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), total glutathione, and 8-isoprostane (8-IP). The effect of NAC on tPA and PAI-1 production was tested in vitro in human mesothelial cells. The effect of NAC on intestinal wound healing was measured using colonic anastomotic burst pressures.
  
  
  RESULTS
  Intraperitoneal NAC reduced adhesions by 53% (P < .001) compared to OP Controls without affecting anastomotic wound healing. NAC increased the tPA/PAI-1 protein ratio and peritoneal fibrinolytic activity by 69% and 127%, respectively, compared to OP Controls (P < .05). NAC did not restore total glutathione levels in peritoneal adhesion tissue but decreased 8-IP by 46% and 65% (P < .05) in peritoneal tissue and fluid, respectively, compared to OP Controls. Human mesothelial cells incubated with NAC exhibited a concentration-dependent increase in the tPA/PAI-1 ratio, which supported in vivo observations (P < .05). Oral NAC did not decrease adhesions.
  
  
  CONCLUSIONS
  NAC administered intraperitoneally decreased adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses without affecting normal anastomotic wound healing. These data suggest a potential new therapeutic use for NAC in adhesion prevention.
authors.affiliation: Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chu
authors.forename: Rizal
authors.initials: R
authors.lastname: Lim
authors.forename: Stanley
authors.initials: S
authors.lastname: Heydrick
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Gainsbury
authors.forename: Rami
authors.initials: R
authors.lastname: Abdou
authors.forename: Laura
authors.initials: L
authors.lastname: D'Addese
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reed
authors.forename: Arthur F
authors.initials: AF
authors.lastname: Stucchi
authors.forename: James M
authors.initials: JM
authors.lastname: Becker
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects; D010537:Peritoneum / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000267:Tissue Adhesions / Q000378:metabolism* / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000975:Antioxidants; D017395:Plasminogen Activator Inhibitor 1; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D010959:Tissue Plasminogen Activator; D005978:Glutathione; D000111:Acetylcysteine