Involvement of the TGF-β pathway in epithelial-mesenchymal transition promoted by the pulmonary microenvironment in Mycoplasma pneumoniae pneumonia

Authors

  • Lu Fan Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Children's Hospital of Jiangnan University, Wuxi, 214000, China https://orcid.org/0009-0003-1916-1672
  • Huixia Wang Department of Pediatric Respiratory Medicine, Pediatric Respiratory Medicine of Zhumadian Central Hospital, Zhumadian, 463000, China
  • Nuo Xu Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Wuxi Peoples’ Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, 214000, China https://orcid.org/0009-0004-3370-3279
  • Yun Guo 1. Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Children's Hospital of Jiangnan University, Wuxi, 214000, China; 2. Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Wuxi Peoples’ Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, 214000, China https://orcid.org/0000-0002-8107-0507
  • Ling li 1. Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Children's Hospital of Jiangnan University, Wuxi, 214000, China; 2. Department of Respiratory Medicine and Clinical Allergy Center, The Affiliated Wuxi Peoples’ Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, 214000, China https://orcid.org/0000-0001-7487-135X

DOI:

https://doi.org/10.2298/ABS240720033F

Keywords:

Mycoplasma pneumoniae pneumonia (MPP), atelectasis, microenvironment, epithelial-mesenchymal transition (EMT), TGF-β

Abstract

Paper description:

  • Mycoplasma pneumoniae pneumonia (MPP) can lead to atelectasis and even pulmonary fibrosis, the rationale for which is unclear.
  • Transcriptome sequencing, immunohistochemistry, Western blotting, immunofluorescence, and ELISA were used to assess whether the pulmonary microenvironment in MPP patients with atelectasis induces epithelial-mesenchymal transition (EMT), and to investigate the signaling pathways involved.
  • The TGF-β, p53, Hippo, and Rap1 pathways were upregulated; the differentially expressed genes were enriched in the TGF-β signaling pathway.
  • EMT induced by BALF from MPP patients with atelectasis is closely related to the TGF-β signaling pathway, which may be one of the mechanisms leading to long-term pulmonary fibrosis.

Abstract: Mycoplasma pneumoniae (MP), one of the smallest prokaryotic microorganisms capable of independent survival, causes respiratory tract infections and various extrapulmonary diseases. Mycoplasma pneumoniae pneumonia (MPP) is the most significant clinical manifestation, often leading to complications such as atelectasis and pulmonary fibrosis. We explored the role of the pulmonary microenvironment in regulating epithelial-mesenchymal transition (EMT) in MPP patients with atelectasis. Transcriptome sequencing revealed significant upregulation of pathways including transforming growth factor beta (TGF-β), tumor protein 53 (P53), protein kinase Hippo, Ras-proximate-1 or Ras-related protein 1 (Rap1), and members of class O forkhead box proteins (FoxO) in cells exposed to bronchoalveolar lavage fluid (BALF) from MPP patients with atelectasis. Among these, the TGF-β pathway exhibited the most pronounced changes in gene expression. Further analysis confirmed that BALF from these patients induced EMT in human bronchial epithelial cells and mouse lung tissues and that TGF-β receptor kinase inhibitor (TRKI) effectively reversed this process. In conclusion, the pulmonary microenvironment in MPP patients with atelectasis promotes EMT in the lungs, with TGF-β playing a key role in this process. This may represent a crucial mechanism contributing to pulmonary fibrosis, underscoring the need to focus on the pulmonary microenvironment and TGF-β-targeted therapies for the prevention and management of pulmonary fibrosis in these patients.

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References

Beeton ML, Zhang XS, Uldum SA, Bebear C, Dumke R, Gullsby K, Ieven M, Loens K, Nir-Paz R, Pereyre S, Spiller OB, Chalker VJ, Mycoplasma ESGf, Chlamydia Infections Mycoplasma pneumoniae s, Mycoplasma ESGf, Chlamydia Infections Mycoplasma pneumoniae subgroup members not listed as an individual a. Mycoplasma pneumoniae infections, 11 countries in Europe and Israel, 2011 to 2016. Euro Surveill. 2020;25(2). https://doi.org/10.2807/1560-7917.ES.2020.25.2.1900112

Guo DX, Hu WJ, Wei R, Wang H, Xu BP, Zhou W, Ma SJ, Huang H, Qin XG, Jiang Y, Dong XP, Fu XY, Shi DW, Wang LY, Shen AD, Xin DL. Epidemiology and mechanism of drug resistance of Mycoplasma pneumoniae in Beijing, China: A multicenter study. Bosn J Basic Med Sci. 2019;19(3):288-96. https://doi.org/10.17305/bjbms.2019.4053

Go JR, Ali NS, Berbari EF. Mycoplasma pneumoniae-Induced Rash and Mucositis. Mayo Clin Proc. 2021;96(6):1520-1. https://doi.org/10.1016/j.mayocp.2021.03.009

Chen S, Ding Y, Vinturache A, Gu H, Lu M, Ding G. Pulmonary embolism associated with mycoplasma in a child. Lancet Infect Dis. 2020;20(11):1347. https://doi.org/10.1016/S1473-3099(20)30253-X

Song WJ, Kang B, Lee HP, Cho J, Lee HJ, Choe YH. Pediatric Mycoplasma pneumoniae Infection Presenting with Acute Cholestatic Hepatitis and Other Extrapulmonary Manifestations in the Absence of Pneumonia. Pediatr Gastroenterol Hepatol Nutr. 2017;20(2):124-9. https://doi.org/10.5223/pghn.2017.20.2.124

Hubert D, Dumke R, Weichert S, Welker S, Tenenbaum T, Schroten H. Emergence of Macrolide-Resistant Mycoplasma pneumoniae during an Outbreak in a Primary School: Clinical Characterization of Hospitalized Children. Pathogens. 2021;10(3). https://doi.org/10.3390/pathogens10030328

Wang X, Zhong LJ, Chen ZM, Zhou YL, Ye B, Zhang YY. Necrotizing pneumonia caused by refractory Mycoplasma pneumonia pneumonia in children. World J Pediatr. 2018;14(4):344-9. https://doi.org/10.1007/s12519-018-0162-6

Xu Q, Zhang L, Hao C, Jiang W, Tao H, Sun H, Huang L, Zhou J, Fan L. Prediction of Bronchial Mucus Plugs Formation in Patients with Refractory Mycoplasma Pneumoniae Pneumonia. J Trop Pediatr. 2017;63(2):148-54. https://doi.org/10.1093/tropej/fmw064

Piccione J, Hysinger EB, Vicencio AG. Pediatric advanced diagnostic and interventional bronchoscopy. Semin Pediatr Surg. 2021;30(3):151065. https://doi.org/10.1016/j.sempedsurg.2021.151065

Su DQ, Li JF, Zhuo ZQ. Clinical Analysis of 122 Cases with Mycoplasma Pneumonia Complicated with Atelectasis: A Retrospective Study. Adv Ther. 2020;37(1):265-71. https://doi.org/10.1007/s12325-019-01129-8

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8. https://doi.org/10.1172/JCI39104

Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A. 2011;108(52):E1475-83. https://doi.org/10.1073/pnas.1117988108

Lee HW, Jose CC, Cuddapah S. Epithelial-mesenchymal transition: Insights into nickel-induced lung diseases. Semin Cancer Biol. 2021;76:99-109. https://doi.org/10.1016/j.semcancer.2021.05.020

Garcia-Cuellar CM, Santibanez-Andrade M, Chirino YI, Quintana-Belmares R, Morales-Barcenas R, Quezada-Maldonado EM, Sanchez-Perez Y. Particulate Matter (PM(10)) Promotes Cell Invasion through Epithelial-Mesenchymal Transition (EMT) by TGF-beta Activation in A549 Lung Cells. Int J Mol Sci. 2021;22(23). https://doi.org/10.3390/ijms222312632

Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;166(1):21-45. https://doi.org/10.1016/j.cell.2016.06.028

Vizarraga D, Kawamoto A, Matsumoto U, Illanes R, Perez-Luque R, Martin J, Mazzolini R, Bierge P, Pich OQ, Espasa M, Sanfeliu I, Esperalba J, Fernandez-Huerta M, Scheffer MP, Pinyol J, Frangakis AS, Lluch-Senar M, Mori S, Shibayama K, Kenri T, Kato T, Namba K, Fita I, Miyata M, Aparicio D. Immunodominant proteins P1 and P40/P90 from human pathogen Mycoplasma pneumoniae. Nat Commun. 2020;11(1):5188. https://doi.org/10.1038/s41467-020-18777-y

Grosshennig S, Ischebeck T, Gibhardt J, Busse J, Feussner I, Stulke J. Hydrogen sulfide is a novel potential virulence factor of Mycoplasma pneumoniae: characterization of the unusual cysteine desulfurase/desulfhydrase HapE. Mol Microbiol. 2016;100(1):42-54. https://doi.org/10.1111/mmi.13300

Becker A, Kannan TR, Taylor AB, Pakhomova ON, Zhang Y, Somarajan SR, Galaleldeen A, Holloway SP, Baseman JB, Hart PJ. Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae. Proc Natl Acad Sci U S A. 2015;112(16):5165-70. https://doi.org/10.1073/pnas.1420308112

Zheng S, Wang Q, D'Souza V, Bartis D, Dancer R, Parekh D, Gao F, Lian Q, Jin S, Thickett DR. ResolvinD(1) stimulates epithelial wound repair and inhibits TGF-beta-induced EMT whilst reducing fibroproliferation and collagen production. Lab Invest. 2018;98(1):130-40. https://doi.org/10.1038/labinvest.2017.114

Shi J, Ma C, Hao X, Luo H, Li M. Reserve of Wnt/β-catenin Signaling Alleviates Mycoplasma pneumoniae P1-C-induced Inflammation in airway epithelial cells and lungs of mice. Mol Immunol. 2023;153:60-74. https://doi.org/10.1016/j.molimm.2022.11.003

Sakai S, Ohhata T, Kitagawa K, Uchida C, Aoshima T, Niida H, Suzuki T, Inoue Y, Miyazawa K, Kitagawa M. Long Noncoding RNA ELIT-1 Acts as a Smad3 Cofactor to Facilitate TGFβ/Smad Signaling and Promote Epithelial-Mesenchymal Transition. Cancer Res. 2019;79(11):2821-38. https://doi.org/10.1158/0008-5472.Can-18-3210

Pittet LF, Bertelli C, Scherz V, Rochat I, Mardegan C, Brouillet R, Jaton K, Mornand A, Kaiser L, Posfay-Barbe K, Asner SA, Greub G. Chlamydia pneumoniae and Mycoplasma pneumoniae in children with cystic fibrosis: impact on bacterial respiratory microbiota diversity. Pathog Dis. 2021;79(1). https://doi.org/10.1093/femspd/ftaa074

Tablan OC, Reyes MP. Chronic interstitial pulmonary fibrosis following Mycoplasma pneumoniae pneumonia. Am J Med. 1985;79(2):268-70. https://doi.org/10.1016/0002-9343(85)90021-x

Lin Y, Tan D, Kan Q, Xiao Z, Jiang Z. The Protective Effect of Naringenin on Airway Remodeling after Mycoplasma Pneumoniae Infection by Inhibiting Autophagy-Mediated Lung Inflammation and Fibrosis. Mediators Inflamm. 2018;2018:8753894. https://doi.org/10.1155/2018/8753894

Gazzillo A, Polidoro MA, Soldani C, Franceschini B, Lleo A, Donadon M. Relationship between Epithelial-to-Mesenchymal Transition and Tumor-Associated Macrophages in Colorectal Liver Metastases. Int J Mol Sci. 2022;23(24). https://doi.org/10.3390/ijms232416197

Ma Z, Lou S, Jiang Z. PHLDA2 regulates EMT and autophagy in colorectal cancer via the PI3K/AKT signaling pathway. Aging (Albany NY). 2020;12(9):7985-8000. https://doi.org/10.18632/aging.103117

Hogea SP, Tudorache E, Pescaru C, Marc M, Oancea C. Bronchoalveolar lavage: role in the evaluation of pulmonary interstitial disease. Expert Rev Respir Med. 2020;14(11):1117-30. https://doi.org/10.1080/17476348.2020.1806063

Meyer KC. Bronchoalveolar lavage as a diagnostic tool. Semin Respir Crit Care Med. 2007;28(5):546-60. https://doi.org/10.1055/s-2007-991527

Efared B, Ebang-Atsame G, Rabiou S, Diarra AS, Tahiri L, Hammas N, Smahi M, Amara B, Benjelloun MC, Serraj M, Chbani L, El Fatemi H. The diagnostic value of the bronchoalveolar lavage in interstitial lung diseases. J Negat Results Biomed. 2017;16(1):4. https://doi.org/10.1186/s12952-017-0069-0

Jing Y, Chen L, Geng L, Shan Z, Yang J. The levels of vitamins and cytokines in serum of elderly patients with community-acquired pneumonia: A case-control study. Health Sci Rep. 2023;6(12):e1737. https://doi.org/10.1002/hsr2.1737

Harada T, Nabeshima K, Hamasaki M, Uesugi N, Watanabe K, Iwasaki H. Epithelial-mesenchymal transition in human lungs with usual interstitial pneumonia: quantitative immunohistochemistry. Pathol Int. 2010;60(1):14-21. https://doi.org/10.1111/j.1440-1827.2009.02469.x

Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006;103(35):13180-5. https://doi.org/10.1073/pnas.0605669103

Tan WJ, Tan QY, Wang T, Lian M, Zhang L, Cheng ZS. Calpain 1 regulates TGF-β1-induced epithelial-mesenchymal transition in human lung epithelial cells via PI3K/Akt signaling pathway. Am J Transl Res. 2017;9(3):1402-9.

Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest. 2009;119(4):772-87. https://doi.org/10.1172/jci33950

Foster KA, Oster CG, Mayer MM, Avery ML, Audus KL. Characterization of the A549 cell line as a type II pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998;243(2):359-66. https://doi.org/10.1006/excr.1998.4172

Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP. In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst. 1973;51(5):1417-23. https://doi.org/10.1093/jnci/51.5.1417

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442-54. https://doi.org/10.1038/nrc822

Zoz DF, Lawson WE, Blackwell TS. Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction. Am J Med Sci. 2011;341(6):435-8. https://doi.org/10.1097/MAJ.0b013e31821a9d8e

Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ. A central role for cadherin signaling in cancer. Exp Cell Res. 2017;358(1):78-85. https://doi.org/10.1016/j.yexcr.2017.04.006

Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807-16. https://doi.org/10.2353/ajpath.2007.070112

Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors. 2011;29(5):196-202. https://doi.org/10.3109/08977194.2011.595714

Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349-63. https://doi.org/10.1038/nrm809

Desmoulière A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 2005;13(1):7-12. https://doi.org/10.1111/j.1067-1927.2005.130102.x

Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128-34. https://doi.org/10.1038/nrc.2017.118

García-Cuellar CM, Santibáñez-Andrade M, Chirino YI, Quintana-Belmares R, Morales-Bárcenas R, Quezada-Maldonado EM, Sánchez-Pérez Y. Particulate Matter (PM(10)) Promotes Cell Invasion through Epithelial-Mesenchymal Transition (EMT) by TGF-β Activation in A549 Lung Cells. Int J Mol Sci. 2021;22(23). https://doi.org/10.3390/ijms222312632

Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016;35(4):645-54. https://doi.org/10.1007/s10555-016-9648-7

Wang X, Eichhorn PJA, Thiery JP. TGF-β, EMT, and resistance to anti-cancer treatment. Semin Cancer Biol. 2023;97:1-11. https://doi.org/10.1016/j.semcancer.2023.10.004

Liu LC, Tsao TC, Hsu SR, Wang HC, Tsai TC, Kao JY, Way TD. EGCG inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition via the inhibition of Smad2 and Erk1/2 signaling pathways in nonsmall cell lung cancer cells. J Agric Food Chem. 2012;60(39):9863-73. https://doi.org/10.1021/jf303690x

Hwang JS, Lai TH, Ahmed M, Pham TM, Elashkar O, Bahar E, Kim DR. Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells. Cancers (Basel). 2022;14(19). https://doi.org/10.3390/cancers14194845

Gao M, Wang K, Yang M, Meng F, Lu R, Zhuang H, Cheng G, Wang X. Transcriptome Analysis of Bronchoalveolar Lavage Fluid From Children With Mycoplasma pneumoniae Pneumonia Reveals Natural Killer and T Cell-Proliferation Responses. Front Immunol. 2018;9:1403. https://doi.org/10.3389/fimmu.2018.01403

Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82(1-2):85-91. https://doi.org/10.1016/s0165-2478(02)00023-8

Miyazono K, Katsuno Y, Koinuma D, Ehata S, Morikawa M. Intracellular and extracellular TGF-β signaling in cancer: some recent topics. Front Med. 2018;12(4):387-411. https://doi.org/10.1007/s11684-018-0646-8

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2024-12-20

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Fan L, Wang H, Xu N, Guo Y, li L. Involvement of the TGF-β pathway in epithelial-mesenchymal transition promoted by the pulmonary microenvironment in Mycoplasma pneumoniae pneumonia. Arch Biol Sci [Internet]. 2024Dec.20 [cited 2024Dec.21];76(4):431-44. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/10082

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Vol. 76 No. 4 (2024)

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Copyright (c) 2024 Lu Fan, Huixia Wang, Nuo Xu, Yun Guo, Ling li

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