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2000
Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Objectives

Intra-abdominal adhesions are the most frequently occurring postoperative complication following abdominopelvic surgery. Peritoneal adhesion formation can lead to infertility, chronic pelvic pain, and intestinal obstruction. Several studies have shown the potential role of metformin in reducing inflammation. Here, we explored the therapeutic potency of Metformin against postsurgical adhesion band formation.

Methods

We adopted Animal Research: Reporting of Experiments (ARRIVE) guidelines for the experimental protocol. Peritoneal adhesions were examined macroscopically. Metformin (100 mg/kg) was administered intraperitoneally in male albino Wistar rats. After 9 days, macroscopic evidence and score of fibrotic bands based on scaling methods were performed and evaluated by the Nair and Leach scoring system. Moreover, the anti-inflammatory and antifibrosis effects were investigated by using hematoxylin and eosin, Masson's trichrome staining, the enzyme-linked immunosorbent assay (ELISA), and reverse transcription polymerase chain reaction (RT-PCR).

Results

Metformin inhibited the stabilization of adhesion bands and appeared to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that metformin prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic gene expression at the peritoneum adhesion tissues modulation of Col 1A1/A3.

Conclusion

These results supported the potential application of metformin in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in patients post-surgery.

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References

  1. GaoQ. WeiG. WuY. YaoN. ZhouC. WangK. WangK. SunX. LiX. Paeoniflorin prevents postoperative peritoneal adhesion formation in an experimental rat model.Oncotarget2017855938999391110.18632/oncotarget.21333 29212197
    [Google Scholar]
  2. TsauoJ. SongH.Y. ChoiE.Y. KimD.K. KimK.Y. ParkJ.H. KimM.T. YoonS.H. LimY.J. EW-7197, an oral transforming growth factor β type I receptor kinase inhibitor, for preventing peritoneal adhesion formation in a rat model.Surgery201816451100110810.1016/j.surg.2018.07.005 30172565
    [Google Scholar]
  3. KreschA.J. SeiferD.B. SachsL.B. BarreseI. Laparoscopy in 100 women with chronic pelvic pain.Obstet. Gynecol.1984645672674 6238250
    [Google Scholar]
  4. OkabayashiK. AshrafianH. ZacharakisE. HasegawaH. KitagawaY. AthanasiouT. DarziA. Adhesions after abdominal surgery: A systematic review of the incidence, distribution and severity.Surg. Today201444340542010.1007/s00595‑013‑0591‑8 23657643
    [Google Scholar]
  5. ten BroekR.P.G. StommelM.W.J. StrikC. van LaarhovenC.J.H.M. KeusF. van GoorH. Benefits and harms of adhesion barriers for abdominal surgery: A systematic review and meta-analysis.Lancet20143839911485910.1016/S0140‑6736(13)61687‑6 24075279
    [Google Scholar]
  6. MorisD. ChakedisJ. Rahnemai-AzarA.A. WilsonA. HennessyM.M. AthanasiouA. BealE.W. ArgyrouC. FelekourasE. PawlikT.M. Postoperative abdominal adhesions: Clinical significance and advances in prevention and management.J. Gastrointest. Surg.201721101713172210.1007/s11605‑017‑3488‑9 28685387
    [Google Scholar]
  7. ArungW. MeurisseM. DetryO. Pathophysiology and prevention of postoperative peritoneal adhesions.World J. Gastroenterol.201141174545455310.3748/wjg.v17.i41.4545
    [Google Scholar]
  8. AysanE. BektasH. ErsozF. SariS. KaygusuzA. HuqG.E. New and simple approach for preventing postoperative peritoneal adhesions: Do not touch the peritoneum without viscous liquid—a multivariate analysis.Obstet. Gynecol. Int.201220121410.1155/2012/368924 22363347
    [Google Scholar]
  9. HellebrekersB.W.J. Trimbos-KemperT.C.M. TrimbosJ.B.M.Z. EmeisJ.J. KooistraT. Use of fibrinolytic agents in the prevention of postoperative adhesion formation.Fertil. Steril.200074220321210.1016/S0015‑0282(00)00656‑7 10927033
    [Google Scholar]
  10. BraunK.M. DiamondM.P. The biology of adhesion formation in the peritoneal cavity.Semin. Pediatr. Surg.201423633634310.1053/j.sempedsurg.2014.06.004 25459438
    [Google Scholar]
  11. KeyerK. ImlayJ.A. Superoxide accelerates DNA damage by elevating free-iron levels.Proc. Natl. Acad. Sci. USA19969324136351364010.1073/pnas.93.24.13635 8942986
    [Google Scholar]
  12. HeydrickS.J. ReedK.L. CohenP.A. AaronsC.B. GowerA.C. BeckerJ.M. StucchiA.F. Intraperitoneal administration of methylene blue attenuates oxidative stress, increases peritoneal fibrinolysis, and inhibits intraabdominal adhesion formation.J. Surg. Res.2007143231131910.1016/j.jss.2006.11.012 17826794
    [Google Scholar]
  13. SaedG.M. DiamondM.P. Hypoxia-induced irreversible up-regulation of type I collagen and transforming growth factor-β1 in human peritoneal fibroblasts.Fertil. Steril.200278114414710.1016/S0015‑0282(02)03146‑1 12095504
    [Google Scholar]
  14. TomasekJ.J. GabbianiG. HinzB. ChaponnierC. BrownR.A. Myofibroblasts and mechano-regulation of connective tissue remodelling.Nat. Rev. Mol. Cell Biol.20023534936310.1038/nrm809 11988769
    [Google Scholar]
  15. BlobeG.C. SchiemannW.P. LodishH.F. Role of transforming growth factor beta in human disease.N. Engl. J. Med.20003421813501358
    [Google Scholar]
  16. MauvielA. Transforming growth factor-beta: A key mediator of fibrosis.Methods Mol. Med.20051176980 16118446
    [Google Scholar]
  17. VargaJ. PhanS. BrennerD.A. In: Methods and Molecular Medicine.200517
    [Google Scholar]
  18. KheirollahiV. WasnickR.M. BiasinV. Vazquez-ArmendarizA.I. ChuX. MoiseenkoA. WeissA. WilhelmJ. ZhangJ.S. KwapiszewskaG. HeroldS. SchermulyR.T. MariB. LiX. SeegerW. GüntherA. BellusciS. El AghaE. Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis.Nat. Commun.2019101298710.1038/s41467‑019‑10839‑0 31278260
    [Google Scholar]
  19. ShenY. MiaoN. XuJ. GanX. XuD. ZhouL. XueH. ZhangW. LuL. Metformin prevents renal fibrosis in mice with unilateral ureteral obstruction and inhibits ang II-induced ECM production in renal fibroblasts.Int. J. Mol. Sci.201617214610.3390/ijms17020146 26805826
    [Google Scholar]
  20. WangY. WangY. LiY. LuL. PengY. ZhangS. XiaA. Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats.Exp. Ther. Med.2020205110.3892/etm.2020.9144 32934682
    [Google Scholar]
  21. RangarajanS. BoneN.B. ZmijewskaA.A. JiangS. ParkD.W. BernardK. LocyM.L. RaviS. DeshaneJ. MannonR.B. AbrahamE. Darley-UsmarV. ThannickalV.J. ZmijewskiJ.W. Metformin reverses established lung fibrosis in a bleomycin model.Nat. Med.20182481121112710.1038/s41591‑018‑0087‑6 29967351
    [Google Scholar]
  22. YilmazB. AksakalO. GungorT. SirvanL. SutN. KelekciS. SoysalS. MollamahmutogluL. Metformin and atorvastatin reduce adhesion formation in a rat uterine horn model.Reprod. Biomed. Online200918343644210.1016/S1472‑6483(10)60106‑X 19298747
    [Google Scholar]
  23. BillerM.L. TuffsC. BleulM. TranD.T.A. DupovacM. KepplerU. HarnossJ.M. ProbstP. SchneiderM. StrowitzkiM.J. Effect of metformin on HIF-1α signaling and postoperative adhesion formation.J. Am. Coll. Surg.202223461167118010.1097/XCS.0000000000000205 35703816
    [Google Scholar]
  24. AskariV.R. RahimiV.B. ZamaniP. FereydouniN. Rahmanian-DevinP. SahebkarA.H. RakhshandehH. Evaluation of the effects of Iranian propolis on the severity of post operational-induced peritoneal adhesion in rats.Biomed. Pharmacother.20189934635310.1016/j.biopha.2018.01.068 29665643
    [Google Scholar]
  25. NairS.K. B. I. Role of proteolytic enzyme in the prevention of postoperative intraperitoneal adhesions.Arch. Surg.1974
    [Google Scholar]
  26. LeachR.E. B. J. Reduction of postsurgical adhesion formation in the rabbit uterine horn model with use of hyaluronate/carboxymethylcellulose gel.Fertil. Steril.1998
    [Google Scholar]
  27. MadeshM. BalasubramanianK.A. Microtiter plate assay for superoxide dismutase using MTT reduction by superoxide.Indian J. Biochem. Biophys.1998353184188 9803669
    [Google Scholar]
  28. AebiH. Catalase in vitro.Methods Enzymol.198410512112610.1016/S0076‑6879(84)05016‑3 6727660
    [Google Scholar]
  29. HuM.L. Plasma SH and GSH measurement.Methods Enzymol.1994233385387
    [Google Scholar]
  30. ArjmandM. Zahedi-AvvalF. BarnehF. MousaviS.H. Intraperitoneal administration of telmisartan prevents postsurgical adhesion band formation.J. Surg. Res.2020248171181
    [Google Scholar]
  31. DuronJ. Adhesive postoperative small bowel obstruction: incidence and risk factors of recurrence after surgical treatment: A multicenter prospective study.Ann. Surg.2006750757
    [Google Scholar]
  32. GotloibL. WajsbrotV. CupermanY. ShostakA. Acute oxidative stress induces peritoneal hyperpermeability, mesothelial loss, and fibrosis.J. Lab. Clin. Med.20041431314010.1016/j.lab.2003.09.005 14749683
    [Google Scholar]
  33. AmblerD.R. FletcherN.M. DiamondM.P. SaedG.M. Effects of hypoxia on the expression of inflammatory markers IL-6 and TNF-a in human normal peritoneal and adhesion fibroblasts.Syst Biol Reprod Med201258632432910.3109/19396368.2012.713439 23043632
    [Google Scholar]
  34. CavaglieriR.C. DayR.T. FeliersD. AbboudH.E. Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.Mol. Cell. Endocrinol.201541211612210.1016/j.mce.2015.06.006 26067231
    [Google Scholar]
  35. MummidiS. DasN.A. CarpenterA.J. KandikattuH. KrenzM. SiebenlistU. ValenteA.J. ChandrasekarB. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo.J. Mol. Cell. Cardiol.2016989510210.1016/j.yjmcc.2016.07.006 27423273
    [Google Scholar]
  36. KitaY. TakamuraT. MisuH. OtaT. KuritaS. TakeshitaY. UnoM. Matsuzawa-NagataN. KatoK. AndoH. FujimuraA. HayashiK. KimuraT. NiY. OtodaT. MiyamotoK. ZenY. NakanumaY. KanekoS. Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis.PLoS One201279e4305610.1371/journal.pone.0043056 23028442
    [Google Scholar]
  37. ParkC.S. BangB.R. KwonH.S. MoonK.A. KimT.B. LeeK.Y. MoonH.B. ChoY.S. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.Biochem. Pharmacol.201284121660167010.1016/j.bcp.2012.09.025 23041647
    [Google Scholar]
  38. ZhengW. SongJ. ZhangY. ChenS. RuanH. FanC. Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-β signaling.Oncotarget201786010178410179410.18632/oncotarget.21695 29254204
    [Google Scholar]
  39. XiaoH. MaX. FengW. FuY. LuZ. XuM. ShenQ. ZhuY. ZhangY. Metformin attenuates cardiac fibrosis by inhibiting the TGFβ1–Smad3 signalling pathway.Cardiovasc. Res.201087350451310.1093/cvr/cvq066 20200042
    [Google Scholar]
  40. LiL. HuangW. LiK. ZhangK. LinC. HanR. LuC. WangY. ChenH. SunF. HeY. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.Oncotarget2015641436054361910.18632/oncotarget.6186 26497205
    [Google Scholar]
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