Effect of intraperitoneal and systemic sirolimus administration on postoperative peritoneal adhesions in rats

Abstract

Purpose: Consequences and complications due to postsurgical adhesions remain to be substantially high. Perilous complications such as inadvertent enterotomy during reopening of abdomen or bowel obstruction may cause not only morbidity but also mortality. Immunosuppressive drugs seem to have a positive effect on postoperative adhesion prevention. Sirolimus is a carbocyclic, lactone-lactam macrolide antibiotic with immunosuppressive, antitumoral, and antifungal properties. Currently sirolimus has clinical usage in posttransplantation immunosuppression and in coronary and peripheral artery vascular stents on routine basis with a relatively low adverse effect profile. We aimed to define and compare systemic and intraperitoneal effect of sirolimus on postoperative peritoneal adhesions. Methods: Three groups of rats for intraperitoneal sirolimus, systemic sirolimus, and control group have been constituted. A peritoneal adhesion model created on each rat. On postoperative 7. day all rats were surgically explored and evaluated with a macroscopic adhesion scoring system. Results: After macroscopic evaluation scores assessed, there were statistically significant difference between three groups (intraperitoneal sirolimus, oral-systemic sirolimus and control). There was statistically significant difference between intraperitoneal sirolimus and control groups. Conclusion: This study showed that in a rat model intraperitoneal sirolimus administration has significant effect on postoperative adhesion prevention.

Keywords

• Surgery-Induced Tissue Adhesions
• Sirolimus
• Surgical Adhesions

References

1. 1. van Goor H. Consequences and complications of peritoneal adhesions. Colorectal dis. 2007; Oct;9 Suppl 2:25-34.
2. 2. Cheung JPY, Tsang HLH, Cheung JCJ: Adjuvant Therapy for the Reduction of Postoperative Intra-abdominal Adhesion Formation. Asian Journal of Surgery Vol 32, No 3, July 2009
3. 3. Cheong YC, Laird SM, Li TC. Peritoneal healing and adhesion formation/reformation. Human Reproduction Update 2001; Vol.7, No.6 pp. 556-566
4. 4. Wasserberg N, Nunoo-Mensah JW, Ruiz P. The Effect of Immunosuppression on Peritoneal Adhesions Formation After Small Bowel Transplantation in Rats. Journal of Surgical Research 2007; 141, 294–298
5. 5.Prevention of intraabdominal adhesions by local and systemic administration of immunosuppressive drugs. Peker K, Inal A, Sayar I, et al. Iran Red Crescent Med J. 2013 Dec;15(12): e14148.
6. 6. Trepanier DJ, Gallant H, Legatt DF. Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clinical Biochemistry, 1998; Volume 31, Issue 5, July, Pages 345-351
7. 7. Linsky CB, Diamond MP, Cunningham T, B Constantine, DeCherney AH, diZerega GS. Adhesion reduction in a rabbit uterine horn model using an absorbable barrier, TC-7. J Reprod Med 1987; 32:17–20.
8. 8. Kaidi A, Nazal M, Gurmchumelidze T, Ali MA, Dawe EJ, Silva YJ. Preoperative administration of antibodies against tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and their impact on peritoneal adhesion formation. Am Surg 1995; 61, 569-572

9. 9. Lucas P, Warecka D, Young H Lee BY. Formation of abdominal adhesions is inhibited by antibodies to transforming growth factor-beta1. J Surg Res 1996; 65, 135-138
10. 10. Holschneider C, Cristoforoni P, Ghosh K, Punyasavatsut M, Abed E, Montz FJ. Endogenous versus exogenous IL-10 in post-operative intraperitoneal adhesion formation in a murine model. J Surg Res 1997; 70, 138-143
11. 11. Montz F, Holschneider C, Bozuk M, Gotlieb WH, Martinez-Maza O. Interleukin 10: ability to minimize postoperative intraperitoneal adhesion formation in a murine model. Fertil Steril 1994; 61, 1136-1140
12. 12. Saba A, Kaida A, Godziachvili V, Dombi GW, Dawe EJ, Libcke JH, Silva YJ. Effects of IL-6 and its neutralising antibodies on peritoneal adhesions formation and wound healing. Am Surg 1996; 62, 569-772
13. 13. Buyalos RP, Funari VA, Azziz R, Watson JM, Martinez-Maza O. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology. Fertil Steril 1992; 58, 302-306.
14. 14. Kanko M, Ozbudak E, Ozerdem A. Effect of Sirolimus in the Prevention of Adhesions Around Intraabdominal Prosthetic Graft. World J Surg 2006; 30: 1648–1652
15. 15. Maciver AH, McCall MD, Edgar RL, et al. Sirolimus drug-eluting, hydrogel-impregnated polypropylene mesh reduces intra-abdominal adhesion formation in a mouse model. Surgery. 2011 Nov;150(5):907-15.
16. 16. Yelian FD, Shavell VI, Diamond MP. Early demonstration of postoperative adhesions a rodent model. Fertil Steril 2010; Vol. 93, No. 8, May 15
17. 17. L. Holmdahl, B. Risberg, D.E. Beck, et al. Adhesions: pathogenesis and prevention-panel discussion and summary. Eur J Surg Suppl, 577 (1997), pp. 56–62
18. 18. E.S. Harris, R.F. Morgan, G.T. Rodeheaver. Analysis of the kinetics of peritoneal adhesion formation in the rat and evaluation of potential antiadhesive agents. Surgery, 117 (1995), pp. 663–669
19. 19. R.C. Dunn, M. Mohler. Effect of varying days of tissue plasminogen activator therapy on the prevention of postsurgical adhesions in a rabbit model. J Surg Res, 54 (1993), pp. 242–245
20. 20. H. Orita, M. Fukasawa, W. Girgis, G.S. diZerega. Inhibition of postsurgical adhesions in a standardized rabbit model: intraperitoneal treatment with tissue plasminogen activator. Int J Fertil, 36 (1991), pp. 172–177
21. 21. Willems MCM, van der Vliet JA, de Man BM, van der Laak JAWM, Romme RMLM, Hendriks T. Persistent effects of everolimus on strength of experimental wounds in intestine and fascia. Wound Rep Reg (2010) 18 98–104
22. 22. Ekici Y, Emiroglu R, Ozdemir H, Karakayali H, Haberal M. Effect of rapamycine on wound healing: an experimental study. Transplant Proc 2007; 39: 1201–3.