Molecular Mechanisms of Pulmonary Fibrosis: The Interaction of Epithelial-mesenchymal Transition and AMPK Pathways in a Bleomycin-induced Model
-
Omid Sadatpour
,
Hoda Kavosi
,
Mahdi Mahmoudi
,
Mehdi Mohammadi
,
Hiva Saffar
,
Elham Farhadi
,
Mohammad Vodjgani
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive extracellular matrix (ECM) deposition, largely mediated by activated fibroblasts. Epithelial-mesenchymal transition (EMT), regulated by transcription factors such as TGF-β, Twist1, and Snail, is a critical mechanism in fibrosis progression. AMP-activated protein kinase (AMPK) has been implicated in modulating fibrotic pathways, but its role in EMT remains unclear. This study aimed to explore the interaction between EMT and AMPK signaling in pulmonary fibrosis.
A bleomycin-induced pulmonary fibrosis mouse model was used. Histological analysis assessed fibrosis and inflammation, while gene expression (TGF-β, Twist1, Snail) was measured by qPCR. Protein levels of E-cadherin, α-SMA, and phosphorylated AMPK were analyzed using Western blotting to evaluate EMT and AMPK activity.
Bleomycin-treated mice showed significant lung inflammation and fibrosis, particularly in the lower region of the left lung. Gene expression analysis revealed elevated TGF-β, Twist1, and Snail in fibrotic areas. Protein analysis demonstrated increased α-SMA and decreased E-cadherin, confirming EMT induction. Notably, AMPK phosphorylation was significantly reduced in fibrotic regions, occurring concurrently with EMT activation.
These findings indicate an inverse relationship between AMPK signaling and EMT in pulmonary fibrosis. EMT may serve as a direct therapeutic target, either by inhibiting transcription factors such as Snail and Twist1 or by modulating upstream metabolic regulators including AMPK.
1. Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology, and regulation. Mucosal Immunol. 2009;2(2):103-21.
2. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157-79.
3. Moss BJ, Ryter SW, Rosas IO. Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis. Annu Rev Pathol. 2022;17:515-46.
4. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389(10082):1941-52.
5. Spagnolo P, Kropski JA, Jones MG, Lee JS, Rossi G, Karampitsakos T, et al. Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther. 2021;222:107798.
6. Podolanczuk AJ, Thomson CC, Remy-Jardin M, Richeldi L, Martinez FJ, Kolb M, et al. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J. 2023;61(4).
7. Adegunsoye A, Kropski JA, Behr J, Blackwell TS, Corte TJ, Cottin V, et al. Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine. Am J Respir Crit Care Med. 2024;210(4):401-23.
8. Ishida Y, Kuninaka Y, Mukaida N, Kondo T. Immune Mechanisms of Pulmonary Fibrosis with Bleomycin. Int J Mol Sci. 2023;24(4).
9. Mota PC, Soares ML, Vasconcelos CD, Ferreira AC, Lima BA, Manduchi E, et al. Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival. J Mol Med (Berl). 2022;100(9):1341-53.
10. Rosenbloom J, Macarak E, Piera-Velazquez S, Jimenez SA. Human Fibrotic Diseases: Current Challenges in Fibrosis Research. Methods Mol Biol. 2017;1627:1-23.
11. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210.
12. Jia Q, Lei Y, Chen S, Liu S, Wang T, Cheng Y. Circulating inflammatory cytokines and risk of idiopathic pulmonary fibrosis: a Mendelian randomization study. BMC Pulm Med. 2023;23(1):369.
13. Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci. 2021;78(5):2031-57.
14. Bohdziewicz A, Pawlik KK, Maciejewska M, Sikora M, Alda-Malicka R, Czuwara J, et al. Future Treatment Options in Systemic Sclerosis-Potential Targets and Ongoing Clinical Trials. J Clin Med. 2022;11(5).
15. Rokni M, Sadeghi Shaker M, Kavosi H, Shokoofi S, Mahmoudi M, Farhadi E. The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications. Arthritis Res Ther. 2022;24(1):108.
16. Manfioletti G, Fedele M. Epithelial-Mesenchymal Transition (EMT). Int J Mol Sci. 2023;24(14).
17. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
18. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
19. Debnath P, Huirem RS, Dutta P, Palchaudhuri S. Epithelial-mesenchymal transition and its transcription factors. Biosci Rep. 2022;42(1).
20. Gonzalez DM, Medici D. Signaling mechanisms of
the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8.
21. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18.
22. Wang Y, Li S, Zhao J, Li Q, Xu C, Wu H, et al. Snail-mediated partial epithelial-mesenchymal transition augments the differentiation of local lung myofibroblast. Chemosphere. 2021;267:128870.
23. Palumbo-Zerr K, Liebl A, Zerr P, Distler A, Beyer C, Distler O, et al. OP0237 Twist1 Amplifies Canonical TGF-β Signaling in Ssc. Annals of the Rheumatic Diseases. 2014;73:152.
24. Pozharskaya V, Torres-González E, Rojas M, Gal A, Amin M, Dollard S, et al. Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One. 2009;4(10):e7559.
25. Chen Y, Zhao X, Sun J, Su W, Zhang L, Li Y, et al. YAP1/Twist promotes fibroblast activation and lung fibrosis, that conferred by miR-15a loss in IPF. Cell Death Differ. 2019;26(9):1832-44.
26. Zhang K, Flanders KC, Phan SH. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1995;147(2):352-61.
27. Santana A, Saxena B, Noble NA, Gold LI, Marshall BC. Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 1995;13(1):34-44.
28. Saxena M, Balaji SA, Deshpande N, Ranganathan S, Pillai DM, Hindupur SK, et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J Cell Sci. 2018;131(14).
29. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48(4):e224.
30. Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol. 2017;45:31-7.
31. Trefts E, Shaw RJ. AMPK: restoring metabolic homeostasis over space and time. Mol Cell. 2021;81(18):3677-90.
32. Lin SC, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2018;27(2):299-313.
33. Gu X, Han YY, Yang CY, Ji HM, Lan YJ, Bi YQ, et al. Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1. Pharmacol Res. 2021;173:105844.
34. Shihan MH, Sharma S, Cable C, Prathigudupu V, Chen A, Mattis AN, et al. AMPK stimulation inhibits YAP/TAZ signaling to ameliorate hepatic fibrosis. Sci Rep. 2024;14(1):5205.
35. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014;74(17):4783-95.
36. Lee JH, Kim JH, Kim JS, Chang JW, Kim SB, Park JS, et al. AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2013;304(6):F686-97.
37. Redente EF, Jacobsen KM, Solomon JJ, Lara AR, Faubel S, Keith RC, et al. Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2011;301(4):L510-8.
38. Mami-Zadeh H, Solgi R, Carrier J-F, Ghadiri H. Material classification based on Dual-Energy Micro-CT images by the Gaussian mixture model. Journal of Instrumentation. 2022;17(02):P02001.
39. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
40. Babaei H, Alibabrdel M, Asadian S, Siavashi V, Jabarpour M, Nassiri SM. Increased circulation mobilization of endothelial progenitor cells in preterm infants with retinopathy of prematurity. J Cell Biochem. 2018;119(8):6575-83.
41. Asadian S, Alibabrdel M, Daei N, Cheraghi H, Maedeh Jafari S, Noshadirad E, et al. Improved angiogenic activity of endothelial progenitor cells in diabetic patients treated with insulin plus metformin. J Cell Biochem. 2019;120(5):7115-24.
42. Guo F, Xu F, Li S, Zhang Y, Lv D, Zheng L, et al. Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD(+)/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism. Eur J Med Res. 2024;29(1):68.
43. Inui N, Sakai S, Kitagawa M. Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway. Int J Mol Sci. 2021;22(11).
44. Weng CM, Li Q, Chen KJ, Xu CX, Deng MS, Li T, et al. Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis. Biosci Rep. 2020;40(1).
45. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028-40.
46. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med (Berl). 2004;82(3):175-81.
47. Glassberg MK. Overview of idiopathic pulmonary fibrosis, evidence-based guidelines, and recent developments in the treatment landscape. Am J Manag Care. 2019;25(11 Suppl):S195-s203.
48. Chow VA, Gopal AK. Where does transplant fit in the age of targeted therapies? Hematology Am Soc Hematol Educ Program. 2019;2019(1):287-93.
49. Ning X, Zhang K, Wu Q, Liu M, Sun S. Emerging role of Twist1 in fibrotic diseases. J Cell Mol Med. 2018;22(3):1383-91.
50. Valenzi E, Bahudhanapati H, Tan J, Tabib T, Sullivan DI, Nouraie M, et al. Single-Nucleus Chromatin Accessibility Identifies a Critical Role for TWIST1 in IPF Myofibroblast Activity. European Respiratory Journal. 2023:2200474.
51. Yan Z, Ao X, Liang X, Chen Z, Liu Y, Wang P, et al. Transcriptional inhibition of miR-486-3p by BCL6 upregulates Snail and induces epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis. Respir Res. 2022;23(1):104.
52. Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial-mesenchymal transitions. J Biol Chem. 2003;278(23):21113-23.
53. Zhou W, Mo X, Cui W, Zhang Z, Li D, Li L, et al. Nrf2 inhibits epithelial-mesenchymal transition by suppressing Snail expression during pulmonary fibrosis. Sci Rep. 2016;6:38646.
54. Jurado-Aguilar J, Barroso E, Bernard M, Zhang M, Peyman M, Rada P, et al. GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway. Metabolism. 2024;152:155772.
55. Gao J, Ye J, Ying Y, Lin H, Luo Z. Negative regulation of TGF-β by AMPK and implications in the treatment of associated disorders. Acta Biochim Biophys Sin (Shanghai). 2018;50(6):523-31.
56. Ding Y, Wang L, Liu B, Ren G, Okubo R, Yu J, et al. Bryodulcosigenin attenuates bleomycin-induced pulmonary fibrosis via inhibiting AMPK-mediated mesenchymal-epithelial transition and oxidative stress. Phytother Res. 2022;36(10):3911-23.
57. Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121-7.
58. Jin H, Hong S, Woo S, Lee J, Choe T, Kim E, et al. Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition. Cell death & disease. 2012;3(6):e319-e.
59. Liang M, Li JW, Luo H, Lulu S, Calbay O, Shenoy A, et al. Epithelial-Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress. Cells. 2022;11(14).
60. Qiu B, Lawan A, Xirouchaki CE, Yi JS, Robert M, Zhang L, et al. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nat Commun. 2023;14(1):5405.
61. Liang S, Yadav M, Vogel KS, Habib SL. A novel role of snail in regulating tuberin/AMPK pathways to promote renal fibrosis in the new mouse model of type II diabetes. FASEB Bioadv. 2021;3(9):730-43.
62. Li M, Zhang L, Guan T, Huang L, Zhu Y, Wen Y, et al. Energy stress-activated AMPK phosphorylates Snail1 and suppresses its stability and oncogenic function. Cancer Lett. 2024;595:216987.
63. Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk BE, Shaw RJ. An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Mol Cell. 2014;55(3):436-50.
64. Lin H, Li N, He H, Ying Y, Sunkara S, Luo L, et al. AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition. Mol Pharmacol. 2015;88(6):1062-71.
65. Wu X, Xiao X, Chen X, Yang M, Hu Z, Shuai S, et al. Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis. Front Pharmacol. 2022;13:948101.
66. Cieslik KA, Trial J, Entman ML. Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast. J Mol Cell Cardiol. 2017;111:81-5.
67. Zhu YR, Zhang XY, Wu QP, Yu CJ, Liu YY, Zhang YQ. PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth. Front Oncol. 2021;11:659181.
2. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157-79.
3. Moss BJ, Ryter SW, Rosas IO. Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis. Annu Rev Pathol. 2022;17:515-46.
4. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389(10082):1941-52.
5. Spagnolo P, Kropski JA, Jones MG, Lee JS, Rossi G, Karampitsakos T, et al. Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther. 2021;222:107798.
6. Podolanczuk AJ, Thomson CC, Remy-Jardin M, Richeldi L, Martinez FJ, Kolb M, et al. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J. 2023;61(4).
7. Adegunsoye A, Kropski JA, Behr J, Blackwell TS, Corte TJ, Cottin V, et al. Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine. Am J Respir Crit Care Med. 2024;210(4):401-23.
8. Ishida Y, Kuninaka Y, Mukaida N, Kondo T. Immune Mechanisms of Pulmonary Fibrosis with Bleomycin. Int J Mol Sci. 2023;24(4).
9. Mota PC, Soares ML, Vasconcelos CD, Ferreira AC, Lima BA, Manduchi E, et al. Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival. J Mol Med (Berl). 2022;100(9):1341-53.
10. Rosenbloom J, Macarak E, Piera-Velazquez S, Jimenez SA. Human Fibrotic Diseases: Current Challenges in Fibrosis Research. Methods Mol Biol. 2017;1627:1-23.
11. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210.
12. Jia Q, Lei Y, Chen S, Liu S, Wang T, Cheng Y. Circulating inflammatory cytokines and risk of idiopathic pulmonary fibrosis: a Mendelian randomization study. BMC Pulm Med. 2023;23(1):369.
13. Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci. 2021;78(5):2031-57.
14. Bohdziewicz A, Pawlik KK, Maciejewska M, Sikora M, Alda-Malicka R, Czuwara J, et al. Future Treatment Options in Systemic Sclerosis-Potential Targets and Ongoing Clinical Trials. J Clin Med. 2022;11(5).
15. Rokni M, Sadeghi Shaker M, Kavosi H, Shokoofi S, Mahmoudi M, Farhadi E. The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications. Arthritis Res Ther. 2022;24(1):108.
16. Manfioletti G, Fedele M. Epithelial-Mesenchymal Transition (EMT). Int J Mol Sci. 2023;24(14).
17. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
18. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
19. Debnath P, Huirem RS, Dutta P, Palchaudhuri S. Epithelial-mesenchymal transition and its transcription factors. Biosci Rep. 2022;42(1).
20. Gonzalez DM, Medici D. Signaling mechanisms of
the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8.
21. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18.
22. Wang Y, Li S, Zhao J, Li Q, Xu C, Wu H, et al. Snail-mediated partial epithelial-mesenchymal transition augments the differentiation of local lung myofibroblast. Chemosphere. 2021;267:128870.
23. Palumbo-Zerr K, Liebl A, Zerr P, Distler A, Beyer C, Distler O, et al. OP0237 Twist1 Amplifies Canonical TGF-β Signaling in Ssc. Annals of the Rheumatic Diseases. 2014;73:152.
24. Pozharskaya V, Torres-González E, Rojas M, Gal A, Amin M, Dollard S, et al. Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One. 2009;4(10):e7559.
25. Chen Y, Zhao X, Sun J, Su W, Zhang L, Li Y, et al. YAP1/Twist promotes fibroblast activation and lung fibrosis, that conferred by miR-15a loss in IPF. Cell Death Differ. 2019;26(9):1832-44.
26. Zhang K, Flanders KC, Phan SH. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1995;147(2):352-61.
27. Santana A, Saxena B, Noble NA, Gold LI, Marshall BC. Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 1995;13(1):34-44.
28. Saxena M, Balaji SA, Deshpande N, Ranganathan S, Pillai DM, Hindupur SK, et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J Cell Sci. 2018;131(14).
29. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48(4):e224.
30. Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol. 2017;45:31-7.
31. Trefts E, Shaw RJ. AMPK: restoring metabolic homeostasis over space and time. Mol Cell. 2021;81(18):3677-90.
32. Lin SC, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2018;27(2):299-313.
33. Gu X, Han YY, Yang CY, Ji HM, Lan YJ, Bi YQ, et al. Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1. Pharmacol Res. 2021;173:105844.
34. Shihan MH, Sharma S, Cable C, Prathigudupu V, Chen A, Mattis AN, et al. AMPK stimulation inhibits YAP/TAZ signaling to ameliorate hepatic fibrosis. Sci Rep. 2024;14(1):5205.
35. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014;74(17):4783-95.
36. Lee JH, Kim JH, Kim JS, Chang JW, Kim SB, Park JS, et al. AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2013;304(6):F686-97.
37. Redente EF, Jacobsen KM, Solomon JJ, Lara AR, Faubel S, Keith RC, et al. Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2011;301(4):L510-8.
38. Mami-Zadeh H, Solgi R, Carrier J-F, Ghadiri H. Material classification based on Dual-Energy Micro-CT images by the Gaussian mixture model. Journal of Instrumentation. 2022;17(02):P02001.
39. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
40. Babaei H, Alibabrdel M, Asadian S, Siavashi V, Jabarpour M, Nassiri SM. Increased circulation mobilization of endothelial progenitor cells in preterm infants with retinopathy of prematurity. J Cell Biochem. 2018;119(8):6575-83.
41. Asadian S, Alibabrdel M, Daei N, Cheraghi H, Maedeh Jafari S, Noshadirad E, et al. Improved angiogenic activity of endothelial progenitor cells in diabetic patients treated with insulin plus metformin. J Cell Biochem. 2019;120(5):7115-24.
42. Guo F, Xu F, Li S, Zhang Y, Lv D, Zheng L, et al. Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD(+)/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism. Eur J Med Res. 2024;29(1):68.
43. Inui N, Sakai S, Kitagawa M. Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway. Int J Mol Sci. 2021;22(11).
44. Weng CM, Li Q, Chen KJ, Xu CX, Deng MS, Li T, et al. Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis. Biosci Rep. 2020;40(1).
45. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028-40.
46. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med (Berl). 2004;82(3):175-81.
47. Glassberg MK. Overview of idiopathic pulmonary fibrosis, evidence-based guidelines, and recent developments in the treatment landscape. Am J Manag Care. 2019;25(11 Suppl):S195-s203.
48. Chow VA, Gopal AK. Where does transplant fit in the age of targeted therapies? Hematology Am Soc Hematol Educ Program. 2019;2019(1):287-93.
49. Ning X, Zhang K, Wu Q, Liu M, Sun S. Emerging role of Twist1 in fibrotic diseases. J Cell Mol Med. 2018;22(3):1383-91.
50. Valenzi E, Bahudhanapati H, Tan J, Tabib T, Sullivan DI, Nouraie M, et al. Single-Nucleus Chromatin Accessibility Identifies a Critical Role for TWIST1 in IPF Myofibroblast Activity. European Respiratory Journal. 2023:2200474.
51. Yan Z, Ao X, Liang X, Chen Z, Liu Y, Wang P, et al. Transcriptional inhibition of miR-486-3p by BCL6 upregulates Snail and induces epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis. Respir Res. 2022;23(1):104.
52. Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial-mesenchymal transitions. J Biol Chem. 2003;278(23):21113-23.
53. Zhou W, Mo X, Cui W, Zhang Z, Li D, Li L, et al. Nrf2 inhibits epithelial-mesenchymal transition by suppressing Snail expression during pulmonary fibrosis. Sci Rep. 2016;6:38646.
54. Jurado-Aguilar J, Barroso E, Bernard M, Zhang M, Peyman M, Rada P, et al. GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway. Metabolism. 2024;152:155772.
55. Gao J, Ye J, Ying Y, Lin H, Luo Z. Negative regulation of TGF-β by AMPK and implications in the treatment of associated disorders. Acta Biochim Biophys Sin (Shanghai). 2018;50(6):523-31.
56. Ding Y, Wang L, Liu B, Ren G, Okubo R, Yu J, et al. Bryodulcosigenin attenuates bleomycin-induced pulmonary fibrosis via inhibiting AMPK-mediated mesenchymal-epithelial transition and oxidative stress. Phytother Res. 2022;36(10):3911-23.
57. Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121-7.
58. Jin H, Hong S, Woo S, Lee J, Choe T, Kim E, et al. Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition. Cell death & disease. 2012;3(6):e319-e.
59. Liang M, Li JW, Luo H, Lulu S, Calbay O, Shenoy A, et al. Epithelial-Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress. Cells. 2022;11(14).
60. Qiu B, Lawan A, Xirouchaki CE, Yi JS, Robert M, Zhang L, et al. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nat Commun. 2023;14(1):5405.
61. Liang S, Yadav M, Vogel KS, Habib SL. A novel role of snail in regulating tuberin/AMPK pathways to promote renal fibrosis in the new mouse model of type II diabetes. FASEB Bioadv. 2021;3(9):730-43.
62. Li M, Zhang L, Guan T, Huang L, Zhu Y, Wen Y, et al. Energy stress-activated AMPK phosphorylates Snail1 and suppresses its stability and oncogenic function. Cancer Lett. 2024;595:216987.
63. Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk BE, Shaw RJ. An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Mol Cell. 2014;55(3):436-50.
64. Lin H, Li N, He H, Ying Y, Sunkara S, Luo L, et al. AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition. Mol Pharmacol. 2015;88(6):1062-71.
65. Wu X, Xiao X, Chen X, Yang M, Hu Z, Shuai S, et al. Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis. Front Pharmacol. 2022;13:948101.
66. Cieslik KA, Trial J, Entman ML. Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast. J Mol Cell Cardiol. 2017;111:81-5.
67. Zhu YR, Zhang XY, Wu QP, Yu CJ, Liu YY, Zhang YQ. PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth. Front Oncol. 2021;11:659181.
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How to Cite
1.
Sadatpour O, Kavosi H, Mahmoudi M, Mohammadi M, Saffar H, Farhadi E, Vodjgani M. Molecular Mechanisms of Pulmonary Fibrosis: The Interaction of Epithelial-mesenchymal Transition and AMPK Pathways in a Bleomycin-induced Model. Iran J Allergy Asthma Immunol. 2025;:1-13.
