Top

Published in:

01-12-2021 | Idiopathic Pulmonary Fibrosis | Research article

Tauroursodeoxycholic acid alleviates pulmonary endoplasmic reticulum stress and epithelial-mesenchymal transition in bleomycin-induced lung fibrosis

Authors: Bin Tong, Lin Fu, Biao Hu, Zhi-Cheng Zhang, Zhu-Xia Tan, Se-Ruo Li, Yuan-Hua Chen, Cheng Zhang, Hua Wang, De-Xiang Xu, Hui Zhao

Published in: BMC Pulmonary Medicine | Issue 1/2021

Abstract

Background

Several studies demonstrate that endoplasmic reticulum (ER) stress-mediated epithelial-mesenchymal transition (EMT) is involved in the process of bleomycin (BLM)-induced pulmonary fibrosis. Tauroursodeoxycholic acid (TUDCA), a bile acid with chaperone properties, is an inhibitor of ER stress. This study aimed to investigate the preventive effects of TUDCA on BLM-induced EMT and lung fibrosis.

Methods

The model of lung fibrosis was established by intratracheal injection with a single dose of BLM (3.0 mg/kg). In TUDCA + BLM group, mice were intraperitoneally injected with TUDCA (250 mg/kg) daily.

Results

BLM-induced alveolar septal destruction and inflammatory cell infiltration were alleviated by TUDCA. BLM-induced interstitial collagen deposition, as determined by Sirius Red staining, was attenuated by TUDCA. BLM-induced elevation of pulmonary α-smooth muscle actin (α-SMA) and reduction of pulmonary E-cadherin were attenuated by TUDCA. BLM-induced pulmonary Smad2/3 phosphorylation was suppressed by TUDCA. BLM-induced elevation of Ki67 and PCNA was inhibited by TUDCA in mice lungs. In addition, BLM-induced elevation of HO-1 (heme oxygenase-1) and 3-NT (3-nitrotyrosine) was alleviated by TUDCA. Finally, BLM-induced upregulation of pulmonary GRP78 and CHOP was attenuated by TUDCA.

Conclusions

These results provide evidence that TUDCA pretreatment inhibits Smad2/3-medited EMT and subsequent lung fibrosis partially through suppressing BLM-induced ER stress and oxidative stress.

Available only for authorised users

Chanda D, Otoupalova E, Smith SR, Volckaert T, De Langhe SP, Thannickal VJ. Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med. 2019;65:56–69. https://doi.org/10.1016/j.mam.2018.08.004.CrossRefPubMed

Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir. 2015;45:1434–45. https://doi.org/10.1183/09031936.00174914.CrossRef

Adamson IY, Bowden DH. The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol. 1974;77:185–98.PubMedPubMedCentral

Rudders RA. Bleomycin: pulmonary toxicity. Ann Intern Med. 1973;78:616–8. https://doi.org/10.7326/0003-4819-78-4-618_1.CrossRef

Mouratis MA, Aidinis V. Modeling pulmonary fibrosis with bleomycin. Curr Opin Pulm Med. 2011;17:355–61. https://doi.org/10.1097/MCP.0b013e328349ac2b.CrossRefPubMed

Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem. 2008;40:362–82. https://doi.org/10.1016/j.biocel.2007.08.011.CrossRef

Chen YL, Zhang X, Bai J, Gai L, Ye XL, Zhang L, et al. Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation. Cell Death Dis. 2013;4:e665. https://doi.org/10.1038/cddis.2013.154.CrossRefPubMedPubMedCentral

Fois AG, Paliogiannis P, Sotgia S, Mangoni AA, Zinellu E, Pirina P, et al. Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review. Respir Res. 2018;19:51. https://doi.org/10.1186/s12931-018-0754-7.CrossRefPubMedPubMedCentral

Cantin AM, North SL, Fells GA, Hubbard RC, Crystal RG. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest. 1987;79:1665–73. https://doi.org/10.1172/JCI113005.CrossRefPubMedPubMedCentral

10.

Teixeira KC, Soares FS, Rocha LG, Silveira PC, Silva LA, Valenca SS, et al. Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm Pharmacol Ther. 2008;21:309–16. https://doi.org/10.1016/j.pupt.2007.07.006.CrossRefPubMed

11.

Aziz M, Matsuda A, Yang WL, Jacob A, Wang P. Milk fat globule-epidermal growth factor-factor 8 attenuates neutrophil infiltration in acute lung injury via modulation of CXCR2. J Immunol. 2012;189:393–402. https://doi.org/10.4049/jimmunol.1200262.CrossRefPubMed

12.

Zhao H, Wu QQ, Cao LF, Qing HY, Zhang C, Chen YH, et al. Melatonin inhibits endoplasmic reticulum stress and epithelial-mesenchymal transition during bleomycin-induced pulmonary fibrosis in mice. PLoS ONE. 2014;9:e97266. https://doi.org/10.1371/journal.pone.0097266.CrossRefPubMedPubMedCentral

13.

Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36:525–31. https://doi.org/10.1053/jhep.2002.36088.CrossRefPubMed

14.

Li P, Fu D, Sheng Q, Yu S, Bao X, Lv Z. TUDCA attenuates intestinal injury and inhibits endoplasmic reticulum stress-mediated intestinal cell apoptosis in necrotizing enterocolitis. Int Immunopharmacol. 2019;74:105665. https://doi.org/10.1016/j.intimp.2019.05.050.CrossRefPubMed

15.

Launay N, Ruiz M, Grau L, Ortega FJ, Ilieva EV, Martínez JJ, et al. Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. Acta Neuropathol. 2017;133:283–301. https://doi.org/10.1007/s00401-016-1655-9.CrossRefPubMed

16.

Shu S, Zhu J, Liu Z, Tang C, Cai J, Dong Z. Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease. EBioMedicine. 2018;37:269–80. https://doi.org/10.1016/j.ebiom.2018.10.006.CrossRefPubMedPubMedCentral

17.

Jiao H, Song J, Sun X, Sun D, Zhong M. Sodium arsenite inhibits lung fibroblast differentiation and pulmonary fibrosis. Pharmacology. 2019;104:368–76. https://doi.org/10.1159/000502536.CrossRefPubMed

18.

Raish M, Ahmad A, Ahmad Ansari M, Ahad A, Al-Jenoobi FI, Al-Mohizea AM, et al. Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats. Biomed Pharmacother. 2018;108:224–31. https://doi.org/10.1016/j.biopha.2018.09.032.CrossRefPubMed

19.

Tan ZX, Chen YH, Xu S, Qin HY, Zhang C, Zhao H, et al. Calcitriol inhibits bleomycin-induced early pulmonary inflammatory response and epithelial-mesenchymal transition in mice. Toxicol Lett. 2016;240:161–71. https://doi.org/10.1016/j.toxlet.2015.10.022.CrossRefPubMed

20.

Fei J, Fu L, Cao W, Hu B, Zhao H, Li JB. Low vitamin D status is associated with epithelial-mesenchymal transition in patients with chronic obstructive pulmonary disease. J Immunol. 2019;203(6):1428–35. https://doi.org/10.4049/jimmunol.1900229.CrossRefPubMed

21.

Fu L, Chen YH, Bo QL, Song YP, Ma L, Wang B, et al. Lipopolysaccharide downregulates 11β-hydroxysteroid dehydrogenase 2 expression through inhibiting peroxisome proliferator-activated receptor-γ in placental trophoblasts. J Immunol. 2019;203(6):1198–207. https://doi.org/10.4049/jimmunol.1900132.CrossRefPubMed

22.

Kim KH, Lee S, Lee H, Shin D, Min D, Kim M, et al. A standardized herbal extract PM014 ameliorates pulmonary fibrosis by suppressing the TGF-β1 pathway. Sci Rep. 2018;8:16860. https://doi.org/10.1038/s41598-018-35320-8.CrossRefPubMedPubMedCentral

23.

Li LC, Li DL, Xu L, Mo XT, Cui WH, Zhao P, et al. High-mobility group box 1 mediates epithelial-to-mesenchymal transition in pulmonary fibrosis involving transforming growth factor-beta1/Smad2/3 signaling. J Pharmacol Exp Ther. 2015;354:302–9. https://doi.org/10.1124/jpet.114.222372.CrossRefPubMed

24.

Andersson-Sjöland A, Karlsson JC, Rydell-Törmänen K. ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling. Lab Invest. 2016;96:206–17. https://doi.org/10.1038/labinvest.2015.100.CrossRefPubMed

25.

Carnesecchi S, Deffert C, Donati Y, Basset O, Hinz B, Preynat-Seauve O, et al. A key role for NOX₄ in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal. 2011;15:607–19. https://doi.org/10.1089/ars.2010.3829.CrossRefPubMedPubMedCentral

26.

Cao SS, Zimmermann EM, Chuang BM, Song B, Nwokoye A, Wilkinson JE, et al. The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. Gastroenterology. 2013;144:989-1000.e6. https://doi.org/10.1053/j.gastro.2013.01.023.CrossRefPubMed

27.

Paridaens A, Raevens S, Devisscher L, Bogaerts E, Verhelst X, Hoorens A, et al. Modulation of the unfolded protein response by tauroursodeoxycholic acid counteracts apoptotic cell death and fibrosis in a mouse model for secondary biliary liver fibrosis. Int J Mol Sci. 2017;18:214. https://doi.org/10.3390/ijms18010214.CrossRefPubMedCentral

28.

Rani S, Sreenivasaiah PK, Kim JO, Lee MY, Kang WS, Kim YS, et al. Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress. PLoS ONE. 2017;12:e0176071. https://doi.org/10.1371/journal.pone.0176071.CrossRefPubMedPubMedCentral

29.

Tanjore H, Cheng DS, Degryse AL, Zoz DF, Abdolrasulnia R, Lawson WE, et al. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem. 2011;286:30972–80. https://doi.org/10.1074/jbc.M110.181164.CrossRefPubMedPubMedCentral

30.

Zhong Q, Zhou B, Ann DK, Minoo P, Liu Y, Banfalvi A, et al. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol. 2011;45:498–509. https://doi.org/10.1165/rcmb.2010-0347OC.CrossRefPubMed

31.

Horowitz JC, Thannickal VJ. Epithelial-mesenchymal interactions in pulmonary fibrosis. Semin Respir Crit Care Med. 2006;27(6):600–12. https://doi.org/10.1055/s-2006-957332.CrossRefPubMedPubMedCentral

32.

Gharaee-Kermani M, Gyetko MR, Hu B, Phan SH. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy. Pharm Res. 2007;224(5):819–41. https://doi.org/10.1007/s11095-006-9216-x.CrossRef

33.

Marudamuthu AS, Bhandary YP, Fan L, Radhakrishnan V, MacKenzie B, Maier E, et al. Caveolin-1-derived peptide limits development of pulmonary fibrosis. Sci Transl Med. 2019;11(522):2848. https://doi.org/10.1126/scitranslmed.aat2848.CrossRef

34.

Kasam RK, Reddy GB, Jegga AG, Madala SK. Dysregulation of mesenchymal cell survival pathways in severe fibrotic lung disease: the effect of nintedanib therapy. Front Pharmacol. 2019;10:532. https://doi.org/10.3389/fphar.2019.00532.CrossRefPubMedPubMedCentral

35.

Lu Y, Azad N, Wang L, Iyer AK, Castranova V, Jiang BH, et al. Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol. 2010;42:432–41. https://doi.org/10.1165/rcmb.2009-0002OC.CrossRefPubMed

36.

Koprivica I, Vujičić M, Gajić D, Saksida T, Stojanović I. Ethyl pyruvate stimulates regulatory T cells and ameliorates type 1 diabetes development in mice. Front Immunol. 2019;9:3130. https://doi.org/10.3389/fimmu.2018.03130.CrossRefPubMedPubMedCentral

37.

Wang L, Feng X, Hu B, Xia Q, Ni X, Song Y. P2X4R promotes airway remodeling by acting on the phenotype switching of bronchial smooth muscle cells in rats. Purinergic Signal. 2018;14(4):433–42. https://doi.org/10.1007/s11302-018-9625-4.CrossRefPubMedPubMedCentral

38.

Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, et al. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep. 2017;7(1):14272. https://doi.org/10.1038/s41598-017-14612-5.CrossRefPubMedPubMedCentral

39.

Mata M, Ruíz A, Cerdá M, Martinez-Losa M, Cortijo J, Santangelo F, et al. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats. Eur Respir J. 2003;22:900–5. https://doi.org/10.1183/09031936.03.00018003.CrossRefPubMed

40.

Hagiwara SI, Ishii Y, Kitamura S. Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit. 2000;162:225–31. https://doi.org/10.1164/ajrccm.162.1.9903129.CrossRef

41.

Shahzeidi S, Sarnstrand B, Jeffery PK, McAnulty RJ, Laurent GJ. Oral N-acetylcysteine reduces bleomycin-induced collagen deposition in the lungs of mice. Eur Respir J. 1991;4:845–52.PubMed

42.

Fonseca I, Gordino G, Moreira S, Nunes MJ, Azevedo C, Gama MJ, et al. Tauroursodeoxycholic acid protects against mitochondrial dysfunction and cell death via mitophagy in human neuroblastoma cells. Mol Neurobiol. 2017;54:6107–19. https://doi.org/10.1007/s12035-016-0145-3.CrossRefPubMed

43.

Oveson BC, Iwase T, Hackett SF, Lee SY, Usui S, Sedlak TW, et al. Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration. J Neurochem. 2011;116:144–53. https://doi.org/10.1111/j.1471-4159.2010.07092.x.CrossRefPubMed

44.

Vendemiale G, Grattagliano I, Signorile A, Altomare E. Ethanol-induced changes of intracellular thiol compartmentation and protein redox status in the rat liver: effect of tauroursodeoxycholate. J Hepatol. 1998;28:46–53. https://doi.org/10.1016/s0168-8278(98)80201-8.CrossRefPubMed

Title: Tauroursodeoxycholic acid alleviates pulmonary endoplasmic reticulum stress and epithelial-mesenchymal transition in bleomycin-induced lung fibrosis
Authors: Bin Tong
Lin Fu
Biao Hu
Zhi-Cheng Zhang
Zhu-Xia Tan
Se-Ruo Li
Yuan-Hua Chen
Cheng Zhang
Hua Wang
De-Xiang Xu
Hui Zhao
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Idiopathic Pulmonary Fibrosis
Published in: BMC Pulmonary Medicine / Issue 1/2021
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-021-01514-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Prediction model for prolonged fever in patients with Mycoplasma pneumoniae pneumonia: a retrospective study of 716 pediatric patients

Factors influencing physical activity in adults with cystic fibrosis

Pneumonia caused by Pseudomonas fluorescens: a case report

LncRNA MANCR positively affects the malignant progression of lung adenocarcinoma

ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial–mesenchymal transition

Systematic review: cystic fibrosis in the SARS-CoV-2/COVID-19 pandemic

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage