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image of YF Reduces Alveolar Epithelial Cell Apoptosis and PF by Inactivating JAK2/STAT3

Abstract

Introduction

Pulmonary fibrosis (PF) is a chronic pulmonary disorder with unknown etiology and an irreversible course. Traditional Chinese medicine (TCM) possesses promising clinical benefits for PF treatment through a multi-component and multi-target approach. This study evaluates the efficacy of Yangyin Yifei Tongluo Wan (YF), a traditional formulation, in the treatment of PF, and further explores the underlying mechanism.

Methods

A bleomycin (BLM)-induced PF mouse model was established. Mice were administered with low-, medium-, and high-dose YF (1.5, 3, and 6 g/kg/d, respectively). The fibrosis degree of mouse lung tissues was evaluated by morphometric measurements and hydroxyproline (HYP) analysis. Network pharmacology-based bioinformatics were employed for constructing a network involving components, targets, and disease, and YF's potential mechanism and molecular targets for PF therapy were explored. This was further validated by TUNEL staining, Western blot, RT-qPCR, and ELISA in BLM-treated mice.

Results

YF could relieve PF in BLM-treated mice in a dose-dependent manner, evidenced by a notable decrease in collagen deposition, and collagen I and III, HYP, fibronectin, vimentin, and α-SMA expressions. Network pharmacology revealed that JAK2/STAT3 signaling pathway-mediated alveolar epithelial cell apoptosis may be a potential therapeutic target for YF in treating PF. assays confirmed that YF's anti-fibrosis effect on BLM-induced PF was ascribed to the suppression of alveolar epithelial cell apoptosis and disruption of the JAK2/STAT3 signaling pathway.

Discussion

YF can block alveolar epithelial cell apoptosis through inactivation of the JAK2/STAT3 signaling, subsequently enhancing the resolution of PF.

Conclusion

YF may be a promising therapeutic candidate for PF treatment.

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2025-09-25
2025-11-02
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References

  1. Koudstaal T. Funke-Chambour M. Kreuter M. Molyneaux P.L. Wijsenbeek M.S. Pulmonary fibrosis: From pathogenesis to clinical decision-making. Trends Mol. Med. 2023 29 12 1076 1087 10.1016/j.molmed.2023.08.010 37716906
    [Google Scholar]
  2. Martinez F.J. Safrin S. Weycker D. The clinical course of patients with idiopathic pulmonary fibrosis. Ann. Intern. Med. 2005 142 963 967 10.7326/0003‑4819‑142‑12_Part_1‑200506210‑00005 15968010
    [Google Scholar]
  3. Richeldi L. Collard H.R. Jones M.G. Idiopathic pulmonary fibrosis. Lancet 2017 389 10082 1941 1952 10.1016/S0140‑6736(17)30866‑8 28365056
    [Google Scholar]
  4. Mathai S.K. Schwartz D.A. Translational research in pulmonary fibrosis. Transl. Res. 2019 209 1 13 10.1016/j.trsl.2019.02.001 30768925
    [Google Scholar]
  5. Savin I.A. Zenkova M.A. Sen’kova A.V. Pulmonary fibrosis as a result of acute lung inflammation: Molecular mechanisms, relevant in vivo models, prognostic and therapeutic approaches. Int. J. Mol. Sci. 2022 23 23 14959 10.3390/ijms232314959 36499287
    [Google Scholar]
  6. Li X. Shen C. Wang L. Pulmonary fibrosis and its related factors in discharged patients with new corona virus pneumonia: A cohort study. Respir. Res. 2021 22 1 203 10.1186/s12931‑021‑01798‑6 34243776
    [Google Scholar]
  7. Bing P. Zhou W. Tan S. Study on the mechanism of astragalus polysaccharide in treating pulmonary fibrosis based on “drug-target-pathway” network. Front. Pharmacol. 2022 13 865065 10.3389/fphar.2022.865065 35370663
    [Google Scholar]
  8. Borok Z. Horie M. Flodby P. Grp78 loss in epithelial progenitors reveals an age-linked role for endoplasmic reticulum stress in pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2020 201 2 198 211 10.1164/rccm.201902‑0451OC 31738079
    [Google Scholar]
  9. Katzen J. Beers M.F. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. J. Clin. Invest. 2020 130 10 5088 5099 10.1172/JCI139519 32870817
    [Google Scholar]
  10. Yue Y.L. Zhang M.Y. Liu J.Y. Fang L.J. Qu Y.Q. The role of autophagy in idiopathic pulmonary fibrosis: From mechanisms to therapies. Ther. Adv. Respir. Dis. 2022 16 17534666221140972 10.1177/17534666221140972 36468453
    [Google Scholar]
  11. Hao Y. Li J. Dan L. Chinese medicine as a therapeutic option for pulmonary fibrosis: Clinical efficacies and underlying mechanisms. J. Ethnopharmacol. 2024 318 116836 10.1016/j.jep.2023.116836
    [Google Scholar]
  12. Wang M. Guan X. Chi Y. Robinson N. Liu J.P. Chinese herbal medicine as adjuvant treatment to chemotherapy for multidrug-resistant tuberculosis (MDR-TB): A systematic review of randomised clinical trials. Tuberculosis (Edinb.) 2015 95 4 364 372 10.1016/j.tube.2015.03.003 25861717
    [Google Scholar]
  13. Zhang Y. Lu P. Qin H. Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential. Biomed. Pharmacother. 2021 133 111072 10.1016/j.biopha.2020.111072 33378971
    [Google Scholar]
  14. Castelo-Soccio L. Kim H. Gadina M. Schwartzberg P.L. Laurence A. O’Shea J.J. Protein kinases: Drug targets for immunological disorders. Nat. Rev. Immunol. 2023 23 12 787 806 10.1038/s41577‑023‑00877‑7 37188939
    [Google Scholar]
  15. Wu Y. Xu J. Xu J. Zheng W. Chen Q. Jiao D. Study on the mechanism of JAK2/STAT3 signaling pathway-mediated inflammatory reaction after cerebral ischemia. Mol. Med. Rep. 2018 17 4 5007 5012 10.3892/mmr.2018.8477 29393445
    [Google Scholar]
  16. Tao Z. Cheng M. Wang S.C. JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats. Int. J. Clin. Exp. Pathol. 2015 8 6 6732 6739 26261556
    [Google Scholar]
  17. Kim H. Kim D. Choi S.A. KDM3A histone demethylase functions as an essential factor for activation of JAK2−STAT3 signaling pathway. Proc. Natl. Acad. Sci. USA 2018 115 46 11766 11771 10.1073/pnas.1805662115 30377265
    [Google Scholar]
  18. Ruan H. Luan J. Gao S. Fedratinib Attenuates Bleomycin-induced pulmonary fibrosis via the JAK2/STAT3 and TGF-β1 Signaling Pathway. Molecules 2021 26 15 4491 10.3390/molecules26154491 34361644
    [Google Scholar]
  19. Bai Y. Liang C. Gao L. Celastrol pyrazine derivative alleviates silicosis progression via inducing ROS-mediated apoptosis in activated fibroblasts. Molecules 2024 29 2 538 10.3390/molecules29020538 38276616
    [Google Scholar]
  20. Ansari Z. Chaurasia A. Neha, Sharma N, Bachheti RK, Gupta PC. Exploring inflammatory and fibrotic mechanisms driving diabetic nephropathy progression. Cytokine Growth Factor Rev. 2025 2 S1359 10.1016/j.cytogfr.2025.05.007 40467395
    [Google Scholar]
  21. Milara J. Hernandez G. Ballester B. The JAK2 pathway is activated in idiopathic pulmonary fibrosis. Respir. Res. 2018 19 1 24 10.1186/s12931‑018‑0728‑9 29409529
    [Google Scholar]
  22. Kim S.J. Cheresh P. Jablonski R. Williams D. Kamp D. The role of mitochondrial DNA in mediating alveolar epithelial cell apoptosis and pulmonary fibrosis. Int. J. Mol. Sci. 2015 16 9 21486 21519 10.3390/ijms160921486 26370974
    [Google Scholar]
  23. Qin Y. Zhao P. Chen Y. Lipopolysaccharide induces epithelial–mesenchymal transition of alveolar epithelial cells cocultured with macrophages possibly via the JAK2/STAT3 signaling pathway. Hum. Exp. Toxicol. 2020 39 2 224 234 10.1177/0960327119881678 31610697
    [Google Scholar]
  24. Wang M.J. Sun Y. Song Y. Mechanism and molecular targets of ejiao siwu decoction for treating primary immune thrombocytopenia based on high-performance liquid chromatograph, network pharmacology, molecular docking and cytokines validation. Front. Med. (Lausanne) 2022 9 891230 10.3389/fmed.2022.891230 35911404
    [Google Scholar]
  25. Jiang Y. Liu N. Zhu S. Hu X. Chang D. Liu J. Elucidation of the mechanisms and molecular targets of yiqi shexue formula for treatment of primary immune thrombocytopenia based on network pharmacology. Front. Pharmacol. 2019 10 1136 10.3389/fphar.2019.01136 31632275
    [Google Scholar]
  26. Yang H. Guo Q. Wu J. Deciphering the effects and mechanisms of yi-fei-san-jie-pill on non-small cell lung cancer with integrating network target analysis and experimental validation. Front. Pharmacol. 2022 13 851554 10.3389/fphar.2022.851554 35645820
    [Google Scholar]
  27. Zhang P. Zhang D. Zhou W. Network pharmacology: Towards the artificial intelligence-based precision traditional Chinese medicine. Brief. Bioinform. 2023 25 1 bbad518 10.1093/bib/bbad518 38197310
    [Google Scholar]
  28. Hu C. Chiang G. Chan A.H.P. A mouse model of volumetric muscle loss and therapeutic scaffold implantation. Nat. Protoc. 2025 20 3 608 619 10.1038/s41596‑024‑01059‑y 39424992
    [Google Scholar]
  29. Zhou S. Yang X. Mo K. Ning Z. Pyroptosis and polarization of macrophages in septic acute lung injury induced by lipopolysaccharide in mice. Immun. Inflamm. Dis. 2024 12 3 e1197 10.1002/iid3.1197 38501547
    [Google Scholar]
  30. Sami M. Kheirandis R. Nasri A. Dabiri S. Application of histochemical and immunohistochemical techniques for detection of lung tissue in cooked sausage. Majallah-i Tahqiqat-i Dampizishki-i Iran 2022 23 2 147 153 10.22099/IJVR.2022.40333.5849 36118605
    [Google Scholar]
  31. Fließer E. Jandl K. Lins T. Lung fibrosis is linked to increased endothelial cell activation and dysfunctional vascular barrier integrity. Am. J. Respir. Cell Mol. Biol. 2024 71 3 318 331 10.1165/rcmb.2024‑0046OC 38843440
    [Google Scholar]
  32. Yang X. Huang X.J. Chen Z. A novel quantification method of lung fibrosis based on Micro-CT images developed with the optimized pulmonary fibrosis mice model induced by bleomycin. Heliyon 2023 9 3 e13598 10.1016/j.heliyon.2023.e13598 36895392
    [Google Scholar]
  33. Zhao Q. Yu J. Zhou H. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct. Target. Ther. 2023 8 1 40 10.1038/s41392‑022‑01219‑0 36710269
    [Google Scholar]
  34. Zhang F. Yu C. Xu W. Identification of critical genes and molecular pathways in COVID-19 myocarditis and constructing gene regulatory networks by bioinformatic analysis. PLoS One 2022 17 6 e0269386 10.1371/journal.pone.0269386 35749386
    [Google Scholar]
  35. Liang Y. Yan Y. Liu N. Wang J. Fang C. Shengxian decoction improves lung function in rats with bleomycin-induced idiopathic pulmonary fibrosis through the inhibition of PANoptosis. J. Ethnopharmacol. 2024 329 118153 10.1016/j.jep.2024.118153 38604513
    [Google Scholar]
  36. Li L.C. Kan L.D. Traditional Chinese medicine for pulmonary fibrosis therapy: Progress and future prospects. J. Ethnopharmacol. 2017 198 45 63 10.1016/j.jep.2016.12.042 28038955
    [Google Scholar]
  37. Zhang M. Wang W. Liu K. Jia C. Hou Y. Bai G. Astragaloside IV protects against lung injury and pulmonary fibrosis in COPD by targeting GTP-GDP domain of RAS and downregulating the RAS/RAF/FoxO signaling pathway. Phytomedicine 2023 120 155066 10.1016/j.phymed.2023.155066 37690229
    [Google Scholar]
  38. Selvaraj V. Sekaran S. Dhanasekaran A. Warrier S. Type 1 collagen: Synthesis, structure and key functions in bone mineralization. Differentiation 2024 136 100757 10.1016/j.diff.2024.100757 38437764
    [Google Scholar]
  39. Jessen H. Hoyer N. Prior T.S. Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis. Respir. Res. 2021 22 1 205 10.1186/s12931‑021‑01801‑0 34261485
    [Google Scholar]
  40. Huang H. Wang X. Zhang X. Wang H. Jiang W. Roxadustat attenuates experimental pulmonary fibrosis in vitro and in vivo. Toxicol. Lett. 2020 331 112 121 10.1016/j.toxlet.2020.06.009 32534005
    [Google Scholar]
  41. Kyung S.Y. Kim D.Y. Yoon J.Y. Sulforaphane attenuates pulmonary fibrosis by inhibiting the epithelial-mesenchymal transition. BMC Pharmacol. Toxicol. 2018 19 1 13 10.1186/s40360‑018‑0204‑7 29609658
    [Google Scholar]
  42. Qian W. Cai X. Qian Q. Zhang W. Wang D. Astragaloside IV modulates TGF ‐β1‐dependent epithelial‐mesenchymal transition in bleomycin‐induced pulmonary fibrosis. J. Cell. Mol. Med. 2018 22 9 4354 4365 10.1111/jcmm.13725 29971947
    [Google Scholar]
  43. Zheng Q. Tong M. Ou B. Liu C. Hu C. Yang Y. Isorhamnetin protects against bleomycin-induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial-mesenchymal transition. Int. J. Mol. Med. 2018 43 1 117 126 10.3892/ijmm.2018.3965 30387812
    [Google Scholar]
  44. Yin Q. Wang W. Cui G. Yan L. Zhang S. Potential role of the Jagged1/Notch1 signaling pathway in the endothelial‐myofibroblast transition during BLM‐induced pulmonary fibrosis. J. Cell. Physiol. 2018 233 3 2451 2463 10.1002/jcp.26122 28776666
    [Google Scholar]
  45. Patten J. Wang K. Fibronectin in development and wound healing. Adv. Drug Deliv. Rev. 2021 170 353 368 10.1016/j.addr.2020.09.005 32961203
    [Google Scholar]
  46. Song C. Xu Z. Liang Q. OGG1 promoted lung fibrosis by activating fibroblasts via interacting with Snail1. Int. Immunopharmacol. 2024 126 111148 10.1016/j.intimp.2023.111148 37977070
    [Google Scholar]
  47. Muro A.F. Moretti F.A. Moore B.B. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2008 177 6 638 645 10.1164/rccm.200708‑1291OC 18096707
    [Google Scholar]
  48. Paulin D. Lilienbaum A. Kardjian S. Agbulut O. Li Z. Vimentin: Regulation and pathogenesis. Biochimie 2022 197 96 112 10.1016/j.biochi.2022.02.003 35151830
    [Google Scholar]
  49. Chen K.J. Li Q. Wen C. Bleomycin (BLM) Induces epithelial-to-mesenchymal transition in cultured A549 Cells via the TGF-β/Smad signaling pathway. J. Cancer 2016 7 11 1557 1564 10.7150/jca.15566 27471572
    [Google Scholar]
  50. dos Santos G. Rogel M.R. Baker M.A. Vimentin regulates activation of the NLRP3 inflammasome. Nat. Commun. 2015 6 1 6574 10.1038/ncomms7574 25762200
    [Google Scholar]
  51. Peng L. Wen L. Shi Q.F. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial–mesenchymal transition and inflammation. Cell Death Dis. 2020 11 11 978 10.1038/s41419‑020‑03178‑2 33188176
    [Google Scholar]
  52. Li Q. Deng M.S. Wang R.T. PD-L1 upregulation promotes drug-induced pulmonary fibrosis by inhibiting vimentin degradation. Pharmacol. Res. 2023 187 106636 10.1016/j.phrs.2022.106636 36586643
    [Google Scholar]
  53. Zhou Y. He Z. Gao Y. Induced pluripotent stem cells inhibit bleomycin-induced pulmonary fibrosis in mice through suppressing TGF-β1/Smad-mediated epithelial to mesenchymal transition. Front. Pharmacol. 2016 7 430 10.3389/fphar.2016.00430 27895584
    [Google Scholar]
  54. Li P. Wu G. Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids 2018 50 1 29 38 10.1007/s00726‑017‑2490‑6 28929384
    [Google Scholar]
  55. Hancock L.A. Hennessy C.E. Solomon G.M. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat. Commun. 2018 9 1 5363 10.1038/s41467‑018‑07768‑9 30560893
    [Google Scholar]
  56. Willis G.R. Fernandez-Gonzalez A. Anastas J. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am. J. Respir. Crit. Care Med. 2018 197 1 104 116 10.1164/rccm.201705‑0925OC 28853608
    [Google Scholar]
  57. Mirzaee S. Mansouri E. Shirani M. Zeinvand-Lorestani M. Khodayar M.J. Diosmin ameliorative effects on oxidative stress and fibrosis in paraquat-induced lung injury in mice. Environ. Sci. Pollut. Res. Int. 2019 26 36 36468 36477 10.1007/s11356‑019‑06572‑2 31732951
    [Google Scholar]
  58. Zhao H. Li C. Li L. Baicalin alleviates bleomycin induced pulmonary fibrosis and fibroblast proliferation in rats via the PI3K/AKT signaling pathway. Mol. Med. Rep. 2020 21 6 2321 2334 10.3892/mmr.2020.11046 32323806
    [Google Scholar]
  59. Baek A.R. Hong J. Song K.S. Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice. Exp. Mol. Med. 2020 52 12 2034 2045 10.1038/s12276‑020‑00545‑z 33318630
    [Google Scholar]
  60. Zhao Q. Jiang D. Sun X. Biomimetic nanotherapy: Core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma. J. Nanobiotechnology 2021 19 1 179 10.1186/s12951‑021‑00922‑4 34120620
    [Google Scholar]
  61. Antonsson B. Bax and other pro-apoptotic Bcl-2 family “killer-proteins” and their victim the mitochondrion. Cell Tissue Res. 2001 306 3 347 361 10.1007/s00441‑001‑0472‑0 11735035
    [Google Scholar]
  62. Moradipour A. Dariushnejad H. Ahmadizadeh C. Lashgarian H.E. Dietary flavonoid carvacrol triggers the apoptosis of human breast cancer MCF-7 cells via the p53/Bax/Bcl-2 axis. Med. Oncol. 2022 40 1 46 10.1007/s12032‑022‑01918‑2 36495389
    [Google Scholar]
  63. Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 2019 20 3 175 193 10.1038/s41580‑018‑0089‑8 30655609
    [Google Scholar]
  64. Zhou P. Wu X. Chen K. Du J. Wang F. Buyang Huanwu decoction ameliorates bleomycin-induced pulmonary fibrosis in rats by attenuating the apoptosis of alveolar type II epithelial cells mediated by endoplasmic reticulum stress. J. Ethnopharmacol. 2024 319 Pt 3 117300 10.1016/j.jep.2023.117300 37813290
    [Google Scholar]
  65. Sahoo G. Samal D. Khandayataray P. Murthy M.K. A Review on Caspases: Key Regulators of Biological Activities and Apoptosis. Mol. Neurobiol. 2023 60 10 5805 5837 10.1007/s12035‑023‑03433‑5 37349620
    [Google Scholar]
  66. Kumar S. Caspase function in programmed cell death. Cell Death Differ. 2007 14 1 32 43 10.1038/sj.cdd.4402060 17082813
    [Google Scholar]
  67. Xu X. An H. Zhang D. A self-illuminating nanoparticle for inflammation imaging and cancer therapy. Sci. Adv. 2019 5 1 eaat2953 10.1126/sciadv.aat2953 30662940
    [Google Scholar]
  68. Liu J. Zhang C. Jia B. Panax notoginseng saponins induce apoptosis in retinoblastoma Y79 cells via the PI3K/AKT signalling pathway. Exp. Eye Res. 2022 216 108954 10.1016/j.exer.2022.108954 35074343
    [Google Scholar]
  69. You X. Jiang X. Zhang C. Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling. Aging (Albany NY) 2022 14 3 1110 1127 10.18632/aging.203874 35120332
    [Google Scholar]
  70. Liu T.T. Sun H.F. Tang M.Z. Bicyclol attenuates pulmonary fibrosis with silicosis via both canonical and non-canonical TGF-β1 signaling pathways. J. Transl. Med. 2024 22 1 682 10.1186/s12967‑024‑05399‑x 39060930
    [Google Scholar]
  71. Hosseini S.A. Zahedipour F. Sathyapalan T. Jamialahmadi T. Sahebkar A. Pulmonary fibrosis: Therapeutic and mechanistic insights into the role of phytochemicals. Biofactors 2021 47 3 250 269 10.1002/biof.1713 33548106
    [Google Scholar]
  72. O’Reilly S. Ciechomska M. Cant R. Hügle T. van Laar J.M. Interleukin-6, its role in fibrosing conditions. Cytokine Growth Factor Rev. 2012 23 3 99 107 10.1016/j.cytogfr.2012.04.003 22561547
    [Google Scholar]
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