Evaluation of Oral Administration of Pirfenidone in Preventing Epidural Fibrosis Formation in Rats

Year 2022, Volume: 23 Issue: 4, 427 - 434, 30.12.2022

Zahir Kızılay , Nesibe Kahraman Çetin , Özge Çevik , Serdar Aktaş , Hakan Öztürk

Abstract

Objective: To investigate the oral administration of pirfenidone on eperidural fibrosis formation (EF).
Materials and Methods: Twenty four rats were divided into three equal groups. Group 1 (control), group 2 (25 mg/kg pirfenidone), and group 3 (50 mg/kg). Thoracic laminectomies were performed in all rats. Pirfenidone was given orally once a day for 30 days. Vertebral column samples were removed surgically at the end of the procedure. EF grading, number of fibroblasts and arachnoidal involvoment were evaluated. TGF-β1 and basic fibroblast growth factor (bFGF) were analyzed using quantitative real-time polymerase chain reaction, and synthesized proteins were examined.
Results: In group 3, EF formation was less than the other groups. The factors in the emergence of antifibrotic activity at 50 mg/kg doses were investigated, and it was revealed that pirfenidone reduced fibroblast proliferation, and showed this effect by reducing TGF-β1 and bFGF expression in fibrotic tissue.
Conclusions: Pirfenidone can be a potential agent for EF treatment.

Keywords

Laminectomy, fibroblast growth factor, transforming growth factor, pirfenidone, epidural fibrosis

References

• 1. Ismailoglu O, Kizilay Z, Cetin NK, Topcu A, Berber O. Effect of curcumin on the formation of epidural fibrosis in an experimental laminectomy model in rats. Turk Neurosurg 2019; 29: 440-4.
• 2. Albinana-Cunningham JN, Ripalda-Cemborain P, Labiano T, Echeveste JI, Granero-Molto F, Alfonso-Olmos M. Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model. J Orthop Surg Res 2018; 13: 72.
• 3. Guler S, Akcali O, Sen B, Micili SC, Sanli NK, Cankaya D. Effect of platelet-rich plasma, fat pad and dural matrix in preventing epidural fibrosis. Acta Ortop Bras 2020; 28: 31-5.
• 4. Sun HH, Wang JC, Feng XM, Zhu SL, Cai J. Allicin inhibits proliferation and promotes apoptosis of human epidural scar fibroblast. World Neurosurg 2020; 136: e460-8.
• 5. Wang S, Li X, Yan L, Nie Q, Dai J, Chen H, et al. Tamoxifen inhibits fibroblast proliferation and prevents epidural fibrosis by regulating the AKT pathway in rats. Biochem Biophys Res Commun 2018; 497: 937-42.
• 6. Demirel E, Yildiz K, Çadirci K, Aygün H, Şenocak E, Gündoğdu B. Effect of platelet-rich fibrin on epidural fibrosis and comparison to ADCON Gel and hyaluronic acid. Acta Orthop Traumatol Turc 2018; 52: 469-74.
• 7. Xu H, Li P, Liu M, Liu C, Sun Z, Guo X, et al. CCN2 and CCN5 exerts opposing effect on fibroblast proliferation and transdifferentiation induced by TFG-β. Clin Exp Pharmacol Physiol 2015; 42: 1207-19.
• 8. Kizilay Z, Cetin NK, Topcu A, Ismailoglu O, Omurlu IK, Aktas S, et al. Effect of etanercept on the formation of epidural fibrosis in an experimental model. Turk Neurosurg 2018; 28: 111-7.
• 9. Zhang C, Kong X, Ning G, Liang Z, Qu T, Chen F, et al. All-trans retinoic acid prevents epidural fibrosis through NF-κB signalling pathway in post-laminectomy rats. Neuropharmacology 2014; 79: 275-81.
• 10. Ozturk Y, Bozkurt I, Yaman ME, Guvenc Y, Tolunay T, Bayram P, et al. Histopathologic analysis of tamoxifen on epidural fibrosis. World Neurosurg 2018; 111: e941-8.
• 11. Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008; 590: 400-8.
• 12. Stahnke T, Kowtharapu BS, Stachs O, Schmitz KP, Wurm J, Wree A, et al. Suppression of TFG-β pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblast in vitro. PLoS One 2017; 12: e0172592.
• 13. Sun YW, Zhang YY, Ke XJ, Wu XJ, Chen ZF, Chi P. Pirfenidone prevents radiation-induced intestinal fibrosis in rats by inhibiting fibroblast proliferation and differentiation and suppressing the TGF-β1/Smad/CTGF signalling pathway. Eur J Pharmacol 2018; 822: 199-206.
• 14. Guo J, Yang Z, Jia Q, Bo C, Shao H, Zhang Z. Pirfenidone inhibits epithelial-mesenchymal transition and pulmonary fibrosis in rat silicosis model. Toxicol Lett 2019; 300: 59-66.
• 15. He Y, Revel M, Loty B. A quantitative model of post-laminectomy scar formation. Effects of a nonsteroidal anti-inflammatory drug. Spine (Phila Pa 1976) 1995; 20: 557-63.
• 16. Hinton JL Jr, Warejcka DJ, Mei Y, McLendon RE, Laurencin C, Lucas PA, et al. Inhibition of epidural scar formation after lumbar laminectomy in the rat. Spine 1995; 20: 564-70.
• 17. Arabacı Tamer S, Yıldırım A, Arabacı Ş, Çiftçi S, Akın S, Sarı E, et al. Treatment with estrogen receptor agonist ERβ improves torsion-induced oxidative testis injury in rats. Life Sci 2019; 222: 203-11.
• 18. Kadıoğlu Yaman B, Çevik Ö, Yalman K, Ertaş B, Şen A, Şener G. Myrtus communis subsp. communis improved cognitive functions in ovariectomized diabetic rats. Gene 2020; 744: 144616.
• 19. Chen F, Zuo Z, Wang K, Zhang C, Gong H, Ye F, et al. Study on salvianolic acid B in the reduction of epidural fibrosis in laminectomy rats. BMC Musculoskelet Disord 2014; 15: 337.
• 20. Tanriverdi O, Erdogan U, Tanik C, Yilmaz I, Gunaldi O, Adilay HU, et al. Impact of sorafenib on epidural fibrosis: An immunohistochemical study. World J Clin Cases 2018; 6: 249-58.
• 21. Dai J, Li X, Yan L, Chen H, He J, Wang S, et al. The effect of suramin on inhibiting fibroblast proliferation and preventing epidural fibrosis after laminectomy in rats. J Orthop Surg Res 2016; 11: 108.
• 22. Liu X, Yang Y, Guo X, Liu L, Wu K, Yu M. The antiangiogenesis effect of pirfenidone in wound healing in vitro. J Ocul Pharmacol Ther 2017; 33: 693-703.
• 23. Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q, et al. Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton) 2017; 22: 589-97.
• 24. Sun Y, Zhang Y, Chi P. Pirfenidone suppresses TGF-β1-induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signalling pathway. Mol Med Rep 2018; 18: 3907-13.
• 25. Shi K, Wang F, Xia J, Zuo B, Wang Z, Cao X. Pirfenidone inhibits epidural scar fibroblast proliferation and differentiation by regulating TGF-β1-induced Smad-dependent and independent pathways. Am J Transl Res 2019; 11: 1593-604.