Elsevier

Surgery

Volume 149, Issue 6, June 2011, Pages 801-812
Surgery

Original Communication
N-acetyl-l-cysteine decreases intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses

Presented in part at the 64th Annual Sessions of the Owen H. Wangensteen Surgical Form on Fundamental Surgical Problems and the 95th Annual Clinical Congress of the American College of Surgeons, Chicago, Illinois, October 11-15, 2009. Abstract published previously in J Am Coll Surg 2009;209:S12
https://doi.org/10.1016/j.surg.2011.02.015Get rights and content

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.

Conclusion

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.

Section snippets

Materials

NAC was obtained from Sigma (catalog no. A7250; St. Louis, MO) and prepared in 0.9% “normal” saline at the stated concentrations.

Animals

Male Wistar rats (range, 200–225 g; Charles River Laboratories, Wilmington, MA) were housed at constant room temperature and under 12-hour light/12-hour dark cycles and allowed access to food and water ad libitum. The Institutional Animal Care and Use Committee at the Boston University School of Medicine approved this study, and all procedures described were performed

Intraperitoneal NAC inhibits adhesion formation

NAC administered intraperitoneally at twice-a-day dosing on preoperative day 1, operative day, and postoperative day 1 (OP + NAC) decreased intraabdominal adhesions by 53% compared to OP Controls (P < .001) (Fig 2, A). In a series of experiments to optimize intraperitoneal NAC dosing by removing pre- or postoperative doses (Table), we were unable to show any decreases in adhesions if we decreased the number of doses. Similarly, increasing a 1-time intraoperative dose of NAC to 300 mg/kg was

Discussion

The data presented here show that NAC administered intraperitoneally, but not orally, decreases intraabdominal adhesions while upregulating peritoneal fibrinolytic activity and antioxidant capacity, with no effect on anastomotic wound healing. NAC is used in a variety of clinical settings but its intraperitoneal administration in adhesion prevention has, to our knowledge, never been studied.

Given its potent antioxidant properties and the mounting evidence that antioxidants decrease adhesions,

References (55)

  • A. Hadaegh et al.

    Effects of hyaluronic acid/carboxymethylcellulose gel on bowel anastomoses in the New Zealand white rabbit

    J Gastrointest Surg

    (1997)
  • D.M. Evans et al.

    Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intra-abdominal adhesions

    Am J Surg

    (1993)
  • A. Jaulmes et al.

    Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells

    Thromb Res

    (2009)
  • S. Kumar et al.

    N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells

    Life Sci

    (2009)
  • J.J. Cheng et al.

    Cyclic strain-induced plasminogen activator inhibitor-1 (PAI-1) release from endothelial cells involves reactive oxygen species

    Biochem Biophys Res Commun

    (1996)
  • S. Kim et al.

    Inhibition of intra-abdominal adhesion formation with the angiogenesis inhibitor sunitinib

    J Surg Res

    (2008)
  • Y. Yeo et al.

    Prevention of peritoneal adhesions with an in situ cross-linkable hyaluronan hydrogel delivering budesonide

    J Control Release

    (2007)
  • O. Koc et al.

    Intraperitoneal administration of single dose type I collagen or low dose melatonin to prevent intraperitoneal adhesion formation: a comparative study

    Eur J Obstet Gynecol Reprod Biol

    (2009)
  • J.L. Hill-West et al.

    Local release of fibrinolytic agents for adhesion prevention

    J Surg Res

    (1995)
  • T. Liakakos et al.

    Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Recent advances in prevention and management

    Dig Surg

    (2001)
  • J.M. Becker et al.

    Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study

    J Am Coll Surg

    (1996)
  • D.M. Wiseman

    Disorders of adhesions or adhesion-related disorder: monolithic entities or part of something bigger–CAPPS?

    Semin Reprod Med

    (2008)
  • K.L. Reed et al.

    A neurokinin-1 receptor antagonist that reduces intra-abdominal adhesion formation decreases oxidative stress in the peritoneum

    Am J Physiol Gastrointest Liver Physiol

    (2007)
  • K.L. Reed et al.

    Pharmacologic inhibition of adhesion formation and peritoneal tissue-type plasminogen activator activity

    Semin Reprod Med

    (2008)
  • L. Holmdahl

    The role of fibrinolysis in adhesion formation

    Eur J Surg Suppl

    (1997)
  • K.L. Reed et al.

    A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity

    Proc Natl Acad Sci USA

    (2004)
  • C.B. Aarons et al.

    Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity

    Ann Surg

    (2007)
  • Cited by (36)

    • Effect of N-acetyl-L-cysteine on inflammation after intraperitoneal mesh placement in a potentially contaminated environment: An experimental study in the rat

      2022, Asian Journal of Surgery
      Citation Excerpt :

      Relevant to our study design, we chose to administer NAC as a single dose in order to accord with a feasible clinical application. In view of collecting more data we set the interval for follow up at 21 days after intervention contrary to a study period of 7 days published by Chu et al.32 In conclusion, our results support the hypothesis that the introduction of NAC intraperitoneally results in a significant decrease in inflammatory reaction and in adhesion formation due to its known anti-inflammatory and fibrinolytic properties.

    • Characterization of peritoneal reactive ascites collected from acute appendicitis and small bowel obstruction patients

      2022, Clinica Chimica Acta
      Citation Excerpt :

      Experimental peritoneal oxidative stress in rats acutely damaged the mesothelium and chronically resulted in fibrosis and bowel ligatures [60]. Increased fibrinolysis in a rat adhesion model was observed upon intraperitoneal administration of the antioxidant, N-acetyl-L-cysteine; however, glutathione levels were not restored [63]. The amino acid central to combating oxidative stress, L-cysteine, was decreased, whereas the oxidized form, L-cystine, was increased in SBO rA compared to appy rA.

    • Combined intraoperative administration of a histone deacetylase inhibitor and a neurokinin-1 receptor antagonist synergistically reduces intra-abdominal adhesion formation in a rat model

      2015, Surgery (United States)
      Citation Excerpt :

      Numerous studies have firmly established that peritoneal fibrinolysis is compromised after surgery, either by a reduction in tPA or an increase in its principal inhibitor, plasminogen activator inhibitor-1,34 or both, indicating that peritoneal fibrin accumulation and stabilization is a key underlying event early in adhesiogenesis.18,31,32,35 Although our previous studies showed that augmenting the peritoneal fibrinolytic system reduced adhesion formation in a rat model,14-16,19 the coadministration of any of these compounds did not increase adhesion prevention, owing in part, to their mechanistic similarities. When we discovered that VPA did not reduce adhesion formation via the fibrinolytic pathway,20 but instead by an alternative mechanism that limited the availability of fibrin substrates, we recognized a potential opportunity to achieve synergistic adhesion reduction by targeting both fibrinolysis with the NK-1RA and fibrin accumulation with VPA (Fig 5, B).

    View all citing articles on Scopus

    Supported in part by research grants from the Smithwick Endowment Fund, Department of Surgery, Boston University School of Medicine, and the Robert and Dana Smith Family Foundation.

    A.F.S. and J.M.B. contributed equally to this publication as senior authors.

    View full text