BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Triamcinolone acetonide alleviates benign biliary stricture by ameliorating biliary fibrosis and inflammation

  • Seyeon Joo (Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • See Young Lee (Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Su Yeon Lee (Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Yeseong Hwang (Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Minki Kim (Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Jae Woong Jeong (Department of Medicine, Yonsei University College of Medicine) ;
  • Sung Ill Jang (Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Sungsoon Fang (Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine)
  • Received : 2023.12.06
  • Accepted : 2024.01.25
  • Published : 2024.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

We conducted a comprehensive series of molecular biological studies aimed at unraveling the intricate mechanisms underlying the anti-fibrotic effects of triamcinolone acetonide (TA) when used in conjunction with fully covered self-expandable metal stents (FCSEMS) for the management of benign biliary strictures (BBS). To decipher the molecular mechanisms responsible for the anti-fibrotic effects of corticosteroids on gallbladder mucosa, we conducted a comprehensive analysis. This analysis included various methodologies such as immunohisto-chemistry, ELISA, real-time PCR, and transcriptome analysis, enabling us to examine alterations in factors related to fibrosis and inflammation at both the protein and RNA levels. Overall, our findings revealed a dose-dependent decrease in fibrosis-related signaling with higher TA concentrations. The 15 mg of steroid treatment (1X) exhibited anti-fibrosis and anti-inflammatory effects after 4 weeks, whereas the 30 mg of steroid treatment (2X) rapidly reduced fibrosis and inflammation within 2 weeks in BBS. Transcriptomic analysis results consistently demonstrated significant downregulation of fibrosis- and inflammation-related pathways and genes in steroid-treated fibroblasts. Use of corticosteroids, specifically TA, together with FCSEMS was effective for the treatment of BBS, ameliorating fibrosis and inflammation. Our molecular biological analysis supports the potential development of steroid-eluted FCSEMS as a therapeutic option for BBS in humans resulting from various surgical procedures.

Keywords

Acknowledgement

This study was funded by the National Research Foundation, Ministry of Science and ICT of Korea (NRF-2020R1A2C1100753) and Research Grant from Gangnam Severance Hospital, Yonsei University College of Medicine (DHHD000105) to S.I.J.; (NRF-2021R1A2C2009749) to S.F.

References

  1. Shimada H, Endo I, Shimada K, Matsuyama R, Kobayashi N and Kubota K (2012) The current diagnosis and treatment of benign biliary stricture. Surg Today 42, 1143-1153 https://doi.org/10.1007/s00595-012-0333-3
  2. Dadhwal U and Kumar V (2012) Benign bile duct strictures. Med J Armed Forces India 68, 299-303 https://doi.org/10.1016/j.mjafi.2012.04.014
  3. Sikora SS, Srikanth G, Agrawal V et al (2008) Liver histology in benign biliary stricture: fibrosis to cirrhosis... and reversal? J Gastroenterol Hepatol 23, 1879-1884 https://doi.org/10.1111/j.1440-1746.2007.04901.x
  4. Geng ZM, Zheng JB, Zhang XX, Tao J and Wang L (2008) Role of transforming growth factor-beta signaling pathway in pathogenesis of benign biliary stricture. World J Gastroenterol 14, 4949
  5. Sanjabi S, Zenewicz LA, Kamanaka M and Flavell RA (2009) Anti-inflammatory and pro-inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 9, 447-453 https://doi.org/10.1016/j.coph.2009.04.008
  6. Siersema PD (2008) Treatment options for esophageal strictures. Nat Clin Pract Gastroenterol Hepatol 5, 142-152 https://doi.org/10.1038/ncpgasthep1053
  7. Yang JD and Yu HC (2021) Prospective control study of clinical effectiveness of prophylactic antibiotics in laparoscopic cholecystectomy on infection rate. Yonsei Med J 62, 172
  8. Heo JY, Lee HS, Son JH, Lee SH and Bang S (2018) Clinical outcomes of bilateral stent-in-stent placement using self-expandable metallic stent for high-grade malignant hilar biliary obstruction. Yonsei Med J 59, 827-833 https://doi.org/10.3349/ymj.2018.59.7.827
  9. Jang SI, Fang S, Nahm JH et al (2022) Preclinical evaluation of endoscopic placement of a steroid-eluting metal stent in an in vivo porcine benign biliary stricture model. Sci Rep 12, 8864
  10. Chen EY, Tan CM, Kou Y et al (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 1-14 https://doi.org/10.1186/1471-2105-14-1
  11. Kuleshov MV, Jones MR, Rouillard AD et al (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44, W90-W97 https://doi.org/10.1093/nar/gkw377
  12. Xie Z, Bailey A, Kuleshov MV et al (2021) Gene set knowledge discovery with Enrichr. Curr Protoc 1, e90
  13. Wan D, Feng J, Wang P, Yang Z and Sun T (2022) Hypoxia-and inflammation-related transcription factor SP3 may be involved in platelet activation and inflammation in intracranial hemorrhage. Front Neurol 13, 886329
  14. Ma MX, Jayasekeran V and Chong AK (2019) Benign biliary strictures: prevalence, impact, and management strategies. Clin Exp Gastroenterol 12, 83-92 https://doi.org/10.2147/CEG.S165016
  15. Qiu Y and Shi R (2019) Roles of steroids in preventing esophageal stricture after endoscopic resection. Can J Gastroenterol Hepatol 2019, 5380815
  16. Seo J and Park JS (2021) Stent flange-induced esophageal stricture treated with an oral steroid. Korean J Med 96, 352-355 https://doi.org/10.3904/kjm.2021.96.4.352
  17. Ismail MS and Charabaty A (2022) Management of Crohn's stricture: medical, endoscopic and surgical therapies. Frontline Gastroenterol 13, 524-530 https://doi.org/10.1136/flgastro-2021-101827
  18. Floman Y and Zor U (1976) Mechanism of steroid action in inflammation: inhibition of prostaglandin synthesis and release. Prostaglandins 12, 403-413 https://doi.org/10.1016/0090-6980(76)90021-6
  19. Bruscoli S, Febo M, Riccardi C and Migliorati G (2021) Glucocorticoid therapy in inflammatory bowel disease: mechanisms and clinical practice. Front Immunol 12, 691480
  20. Richeldi L, Davies HRH, Spagnolo P, Luppi F and Group CA (1996) Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2010, CD002880
  21. Davies H, Richeldi L and Walters E (2003) Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2, CD003134
  22. Adcock I and Lane S (2003) Mechanisms of steroid action and resistance in inflammation. Corticosteroid-insensitive asthma: molecular mechanisms. J Endocrinol 178, 347-355 https://doi.org/10.1677/joe.0.1780347
  23. Barnes PJ (2006) How corticosteroids control inflammation: quintiles prize lecture 2005. Br J Pharmacol 148, 245-254 https://doi.org/10.1038/sj.bjp.0706736
  24. Frew JW and Murrell DF (2012) Corticosteroid use in autoimmune blistering diseases. Immunol Allergy Clin North Am 32, 283-294 https://doi.org/10.1016/j.iac.2012.04.008
  25. Barnes PJ, Adcock I, Spedding M and Vanhoutte PM (1993) Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 14, 436-441 https://doi.org/10.1016/0165-6147(93)90184-L
  26. Czaja AJ and Carpenter HA (2004) Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 40, 646-652 https://doi.org/10.1016/j.jhep.2004.01.009
  27. Czaja AJ and Carpenter HA (2004) Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology 39, 1631-1638 https://doi.org/10.1002/hep.20235
  28. Davis CS, Faino AV, Onchiri F et al (2023) Systemic corticosteroids in the management of pediatric cystic fibrosis pulmonary exacerbations. Ann Am Thorac Soc 20, 75-82 https://doi.org/10.1513/AnnalsATS.202203-201OC
  29. Yang TH, Gingery A, Thoreson AR, Larson DR, Zhao C and Amadio PC (2018) Triamcinolone acetonide affects TGF-β signaling regulation of fibrosis in idiopathic carpal tunnel syndrome. BMC Musculoskelet Disord 19, 1-9 https://doi.org/10.1186/s12891-017-1921-6
  30. Imai S, Otsuka T, Naito A, Shimazawa M and Hara H (2017) Triamcinolone acetonide suppresses inflammation and facilitates vascular barrier function in human retinal microvascular endothelial cells. Curr Neurovasc Res 14, 232-241
  31. Jeon BS, Shin BH, Huh BK et al (2018) Silicone implants capable of the local, controlled delivery of triamcinolone for the prevention of fibrosis with minimized drug side effects. J Ind Eng Chem 63, 168-180 https://doi.org/10.1016/j.jiec.2018.02.013
  32. Grennan D and Wang S (2019) Steroid side effects. JAMA 322, 282-282 https://doi.org/10.1001/jama.2019.8506
  33. Buchman AL (2001) Side effects of corticosteroid therapy. J Clin Gastroenterol 33, 289-294 https://doi.org/10.1097/00004836-200110000-00006