Proton pump inhibitors attenuate myofibroblast formation associated with thyroid eye disease through the aryl hydrocarbon receptor

Autoři: Christine L. Hammond aff001;  Elisa Roztocil aff001;  Richard P. Phipps aff002;  Steven E. Feldon aff001;  Collynn F. Woeller aff001
Působiště autorů: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York, United States of America aff001;  Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222779


Thyroid eye disease (TED) can lead to scar formation and tissue remodeling in the orbital space. In severe cases, the scarring process leads to sight-threatening pathophysiology. There is no known effective way to prevent scar formation in TED patients, or to reverse scarring once it occurs. In this study, we show that the proton pump inhibitors (PPIs), esomeprazole and lansoprazole, can prevent transforming growth factor beta (TGFβ)-mediated differentiation of TED orbital fibroblasts to myofibroblasts, a critical step in scar formation. Both PPIs prevent TGFβ-induced increases in alpha-smooth muscle actin (αSMA), calponin, and collagen production and reduce TED orbital fibroblast cell proliferation and migration. Esomeprazole and lansoprazole exert these effects through an aryl hydrocarbon receptor (AHR)-dependent pathway that includes reducing β-catenin/Wnt signaling. We conclude that PPIs are potentially useful therapies for preventing or treating TED by reducing the myofibroblast accumulation that occurs in the disease.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Connective tissue cells – Fibroblasts – Signal transduction – Cell signaling – Signaling cascades – Wnt signaling cascade – TGF-beta signaling cascade – Anatomy – Biological tissue – Connective tissue – Biochemistry – Proteins – Collagens – Post-translational modification – Phosphorylation – Nucleic acids – RNA – Non-coding RNA – Genetics – Gene expression – Gene regulation – Small interfering RNAs – Molecular biology – Molecular biology techniques – Molecular biology assays and analysis techniques – Gene expression and vector techniques – Protein expression – Medicine and health sciences – Research and analysis methods – Specimen preparation and treatment – Staining – Nuclear staining – DAPI staining


1. Bahn RS. Current Insights into the Pathogenesis of Graves' Ophthalmopathy. Horm Metab Res. 2015;47(10):773–8. Epub 2015/09/12. doi: 10.1055/s-0035-1555762 26361262.

2. Bartalena L. Graves' orbitopathy: imperfect treatments for a rare disease. Eur Thyroid J. 2013;2(4):259–69. Epub 2014/05/02. doi: 10.1159/000356042 24783057; PubMed Central PMCID: PMC3923600.

3. Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol. 2011;22(5):385–90. Epub 2011/07/07. doi: 10.1097/ICU.0b013e3283499446 21730841; PubMed Central PMCID: PMC3512192.

4. Schluter A, Horstmann M, Diaz-Cano S, Plohn S, Stahr K, Mattheis S, et al. Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves' orbitopathy. Clin Exp Immunol. 2018;191(3):255–67. Epub 2017/10/24. doi: 10.1111/cei.13075 29058307; PubMed Central PMCID: PMC5801504.

5. Smith TJ. New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor. F1000Res. 2018;7:134. Epub 2018/05/11. doi: 10.12688/f1000research.12787.1 29744034; PubMed Central PMCID: PMC5795270.

6. Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves' ophthalmopathy. Exp Eye Res. 2016;142:83–91. Epub 2015/12/18. doi: 10.1016/j.exer.2015.02.007 26675405.

7. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017;376(18):1748–61. Epub 2017/05/04. doi: 10.1056/NEJMoa1614949 28467880; PubMed Central PMCID: PMC5718164.

8. Lehmann GM, Xi X, Kulkarni AA, Olsen KC, Pollock SJ, Baglole CJ, et al. The aryl hydrocarbon receptor ligand ITE inhibits TGFbeta1-induced human myofibroblast differentiation. Am J Pathol. 2011;178(4):1556–67. Epub 2011/03/17. doi: 10.1016/j.ajpath.2010.12.025 21406171; PubMed Central PMCID: PMC3078465.

9. Woeller CF, Roztocil E, Hammond CL, Feldon SE, Phipps RP. The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation: Implications for Thyroid Eye Disease. Am J Pathol. 2016;186(12):3189–202. Epub 2016/11/16. doi: 10.1016/j.ajpath.2016.08.017 27842700; PubMed Central PMCID: PMC5225292.

10. Jin UH, Lee SO, Safe S. Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells. J Pharmacol Exp Ther. 2012;343(2):333–41. Epub 2012/08/11. doi: 10.1124/jpet.112.195339 22879383; PubMed Central PMCID: PMC3477220.

11. Roman AC, Carvajal-Gonzalez JM, Merino JM, Mulero-Navarro S, Fernandez-Salguero PM. The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. Pharmacol Ther. 2018;185:50–63. Epub 2017/12/21. doi: 10.1016/j.pharmthera.2017.12.003 29258844.

12. Berardi RR. A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Am J Manag Care. 2000;6(9 Suppl):S491–505. Epub 2000/09/08. 10977489.

13. Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci. 2009;54(11):2312–7. Epub 2009/08/29. doi: 10.1007/s10620-009-0951-9 19714466; PubMed Central PMCID: PMC3035917.

14. Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, et al. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. J Transl Med. 2015;13:249. Epub 2015/08/02. doi: 10.1186/s12967-015-0614-x 26231702; PubMed Central PMCID: PMC4522053.

15. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR. Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007;71(6):1475–86. Epub 2007/03/01. doi: 10.1124/mol.106.032748 17327465.

16. Shivanna B, Chu C, Welty SE, Jiang W, Wang L, Couroucli XI, et al. Omeprazole attenuates hyperoxic injury in H441 cells via the aryl hydrocarbon receptor. Free Radic Biol Med. 2011;51(10):1910–7. Epub 2011/09/13. doi: 10.1016/j.freeradbiomed.2011.08.013 21906671; PubMed Central PMCID: PMC3901644.

17. Shivanna B, Jiang W, Wang L, Couroucli XI, Moorthy B. Omeprazole attenuates hyperoxic lung injury in mice via aryl hydrocarbon receptor activation and is associated with increased expression of cytochrome P4501A enzymes. J Pharmacol Exp Ther. 2011;339(1):106–14. Epub 2011/07/20. doi: 10.1124/jpet.111.182980 21768223; PubMed Central PMCID: PMC3186283.

18. Novotna A, Srovnalova A, Svecarova M, Korhonova M, Bartonkova I, Dvorak Z. Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines. PLoS One. 2014;9(6):e98711. Epub 2014/06/03. doi: 10.1371/journal.pone.0098711 24887303; PubMed Central PMCID: PMC4041848.

19. Yamashita Y, Ueyama T, Nishi T, Yamamoto Y, Kawakoshi A, Sunami S, et al. Nrf2-inducing anti-oxidation stress response in the rat liver—new beneficial effect of lansoprazole. PLoS One. 2014;9(5):e97419. Epub 2014/05/23. doi: 10.1371/journal.pone.0097419 24846271; PubMed Central PMCID: PMC4028208.

20. Hinz B. Myofibroblasts. Exp Eye Res. 2016;142:56–70. Epub 2015/07/21. doi: 10.1016/j.exer.2015.07.009 26192991.

21. Ferguson HE, Kulkarni A, Lehmann GM, Garcia-Bates TM, Thatcher TH, Huxlin KR, et al. Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. Am J Respir Cell Mol Biol. 2009;41(6):722–30. Epub 2009/03/17. doi: 10.1165/rcmb.2009-0006OC 19286977; PubMed Central PMCID: PMC2784409.

22. Ma Q, Baldwin KT. 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. Role of the transcription activaton and DNA binding of AhR. J Biol Chem. 2000;275(12):8432–8. Epub 2000/03/18. doi: 10.1074/jbc.275.12.8432 10722677.

23. Ginter A, Migliori ME. The Role of Biological Agents and Immunomodulators in Treatment Strategies for Thyroid Eye Disease: An Evidence-based Review. R I Med J (2013). 2016;99(6):26–9. Epub 2016/06/02. 27247969.

24. Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, et al. A new highly thyrotropin receptor-selective small molecule antagonist with potential for the treatment of Graves' orbitopathy. Thyroid. 2018. Epub 2018/10/24. doi: 10.1089/thy.2018.0349 30351237.

25. Eltahir HM, Nazmy MH. Esomeprazole ameliorates CCl4 induced liver fibrosis in rats via modulating oxidative stress, inflammatory, fibrogenic and apoptotic markers. Biomed Pharmacother. 2018;97:1356–65. Epub 2017/11/22. doi: 10.1016/j.biopha.2017.11.028 29156525.

26. Nishi T, Yamamoto Y, Yamagishi N, Iguchi M, Tamai H, Ito T, et al. Lansoprazole prevents the progression of liver fibrosis in non-alcoholic steatohepatitis model rats. J Pharm Pharmacol. 2018;70(3):383–92. Epub 2018/01/23. doi: 10.1111/jphp.12870 29355950.

27. Nelson C, Lee J, Ko K, Sikora AG, Bonnen MD, Enkhbaatar P, et al. Therapeutic Efficacy of Esomeprazole in Cotton Smoke-Induced Lung Injury Model. Front Pharmacol. 2017;8:16. Epub 2017/02/12. doi: 10.3389/fphar.2017.00016 28184197; PubMed Central PMCID: PMC5266706.

28. Handa O, Yoshida N, Fujita N, Tanaka Y, Ueda M, Takagi T, et al. Molecular mechanisms involved in anti-inflammatory effects of proton pump inhibitors. Inflamm Res. 2006;55(11):476–80. Epub 2006/11/24. doi: 10.1007/s00011-006-6056-4 17122965.

29. Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut. 1992;33(5):617–21. Epub 1992/05/01. doi: 10.1136/gut.33.5.617 1319381; PubMed Central PMCID: PMC1379289.

30. Jin UH, Lee SO, Pfent C, Safe S. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer. 2014;14:498. Epub 2014/07/12. doi: 10.1186/1471-2407-14-498 25011475; PubMed Central PMCID: PMC4226953.

31. Piersma B, Bank RA, Boersema M. Signaling in Fibrosis: TGF-beta, WNT, and YAP/TAZ Converge. Frontiers in medicine. 2015;2:59. Epub 2015/09/22. doi: 10.3389/fmed.2015.00059 26389119; PubMed Central PMCID: PMC4558529.

32. Jeon KI, Kulkarni A, Woeller CF, Phipps RP, Sime PJ, Hindman HB, et al. Inhibitory effects of PPARgamma ligands on TGF-beta1-induced corneal myofibroblast transformation. Am J Pathol. 2014;184(5):1429–45. Epub 2014/03/22. doi: 10.1016/j.ajpath.2014.01.026 24650561; PubMed Central PMCID: PMC4005981.

33. Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–55. Epub 2012/03/06. doi: 10.1016/j.ajpath.2012.02.004 22387320; PubMed Central PMCID: PMC3640252.

34. Wolff S, Harper PA, Wong JM, Mostert V, Wang Y, Abel J. Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1). Mol Pharmacol. 2001;59(4):716–24. Epub 2001/03/22. doi: 10.1124/mol.59.4.716 11259615.

35. Bussmann UA, Baranao JL. Interaction between the aryl hydrocarbon receptor and transforming growth factor-beta signaling pathways: evidence of an asymmetrical relationship in rat granulosa cells. Biochem Pharmacol. 2008;76(9):1165–74. Epub 2008/09/13. doi: 10.1016/j.bcp.2008.08.019 18786509.

36. Gomez-Duran A, Carvajal-Gonzalez JM, Mulero-Navarro S, Santiago-Josefat B, Puga A, Fernandez-Salguero PM. Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling. Biochem Pharmacol. 2009;77(4):700–12. Epub 2008/09/25. doi: 10.1016/j.bcp.2008.08.032 18812170.

37. Puga A, Tomlinson CR, Xia Y. Ah receptor signals cross-talk with multiple developmental pathways. Biochem Pharmacol. 2005;69(2):199–207. Epub 2005/01/04. doi: 10.1016/j.bcp.2004.06.043 15627472.

38. Basu D, Lettan R, Damodaran K, Strellec S, Reyes-Mugica M, Rebbaa A. Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-beta, and Wnt signaling pathways. Mol Cancer Ther. 2014;13(6):1457–67. Epub 2014/04/04. doi: 10.1158/1535-7163.MCT-13-0918 24694946.

39. Morgan JT, Murphy CJ, Russell P. What do mechanotransduction, Hippo, Wnt, and TGFbeta have in common? YAP and TAZ as key orchestrating molecules in ocular health and disease. Exp Eye Res. 2013;115:1–12. Epub 2013/06/25. doi: 10.1016/j.exer.2013.06.012 23792172; PubMed Central PMCID: PMC3795947.

40. Haarmann-Stemmann T, Bothe H, Abel J. Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem Pharmacol. 2009;77(4):508–20. Epub 2008/10/14. doi: 10.1016/j.bcp.2008.09.013 18848820.

41. Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, et al. Interactions between beta-catenin and transforming growth factor-beta signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012;287(10):7026–38. Epub 2012/01/14. doi: 10.1074/jbc.M111.276311 22241478; PubMed Central PMCID: PMC3293544.

42. Sun Z, Wang C, Shi C, Sun F, Xu X, Qian W, et al. Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis. International journal of molecular medicine. 2014;33(5):1097–109. Epub 2014/02/28. doi: 10.3892/ijmm.2014.1672 24573542; PubMed Central PMCID: PMC4020487.

43. Feng S, Zheng Z, Feng L, Yang L, Chen Z, Lin Y, et al. Proton pump inhibitor pantoprazole inhibits the proliferation, selfrenewal and chemoresistance of gastric cancer stem cells via the EMT/betacatenin pathways. Oncology reports. 2016;36(6):3207–14. Epub 2016/10/18. doi: 10.3892/or.2016.5154 27748935.

44. Strand DS, Kim D, Peura DA. 25 Years of Proton Pump Inhibitors: A Comprehensive Review. Gut Liver. 2017;11(1):27–37. Epub 2016/11/15. doi: 10.5009/gnl15502 27840364; PubMed Central PMCID: PMC5221858.

45. Brisebois S, Merati A, Giliberto JP. Proton pump inhibitors: Review of reported risks and controversies. Laryngoscope investigative otolaryngology. 2018;3(6):457–62. Epub 2019/01/02. doi: 10.1002/lio2.187 30599030; PubMed Central PMCID: PMC6302736.

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