Top

BMC Pulmonary Medicine

Published in:

Open Access 01-12-2024 | Idiopathic Pulmonary Fibrosis | Research

Sinomenine attenuates pulmonary fibrosis by downregulating TGF-β1/Smad3, PI3K/Akt and NF-κB signaling pathways

Authors: Fuqiang Yao, Minghao Xu, Lingjun Dong, Xiao Shen, Yujie Shen, Yisheng Jiang, Ting Zhu, Chu Zhang, Guangmao Yu

Published in: BMC Pulmonary Medicine | Issue 1/2024

Abstract

Background

Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most prevalent form. In traditional Chinese medicine, various disorders are treated using Sinomenine (SIN). The SIN’s strategy for PF defense is unclear.

Methods

Bleomycin (BLM) was used to induce PF, after which inflammatory factors, lung histological alterations, and the TGF-/Smad signaling pathway were assessed. By administering various dosages of SIN and the TGF- receptor inhibitor SB-431,542 to human embryonic lung fibroblasts (HFL-1) and A549 cells, we were able to examine proliferation and migration as well as the signaling molecules implicated in Epithelial-Mesenchymal Transition (EMT) and Extra-Cellular Matrix (ECM).

Results

In vivo, SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice. In vitro, SIN inhibited the migration and proliferation by inhibiting TGF-β1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the myofibroblasts (FMT) of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins.

Conclusion

SIN attenuated PF by down-regulating TGF-β/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.

Available only for authorised users

Carabelli AM, Peacock TP, Thorne LG, Harvey WT, Hughes J, Peacock SJ, Barclay WS, de Silva TI, Towers GJ, Robertson DL. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol. 2023;21(3):162–77. https://doi.org/10.1038/s41579-022-00841-7CrossRefPubMedPubMedCentral

Grillo F, Barisione E, Ball L, Mastracci L, Fiocca R. Lung fibrosis: an undervalued finding in COVID-19 pathological series. Lancet Infect Dis. 2021;21(4):e72. https://doi.org/10.1016/s1473-3099(20)30582-xCrossRefPubMed

Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med et maladies Infectieuses. 2020;50(4):382–3. https://doi.org/10.1016/j.medmal.2020.04.002CrossRef

Vassiliou AG, Keskinidou C, Jahaj E, Gallos P, Dimopoulou I, Kotanidou A, Orfanos SE. ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients. Cells. 2021;10(1). https://doi.org/10.3390/cells10010186

Maiese A, Manetti AC, La Russa R, Di Paolo M, Turillazzi E, Frati P, Fineschi V. Autopsy findings in COVID-19-related deaths: a literature review. Forensic Sci Med Pathol. 2021;17(2):279–96. https://doi.org/10.1007/s12024-020-00310-8CrossRefPubMed

George PM, Patterson CM, Reed AK, Thillai M. Lung transplantation for idiopathic pulmonary fibrosis. Lancet Respiratory Med. 2019;7(3):271–82. https://doi.org/10.1016/s2213-2600(18)30502-2CrossRef

Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, Raghu G, Noth I, Garcia CK. Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(3):336–47. https://doi.org/10.1164/rccm.201809-1646OCCrossRefPubMedPubMedCentral

Hewlett JC, Kropski JA, Blackwell TS. Idiopathic pulmonary fibrosis: epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biology: J Int Soc Matrix Biology. 2018. https://doi.org/10.1016/j.matbio.2018.03.021. 71–72:112 – 27.CrossRef

Xia H, Gilbertsen A, Herrera J, Racila E, Smith K, Peterson M, Griffin T, Benyumov A, Yang L, Bitterman PB, Henke CA. Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis. J Clin Investig. 2017;127(7):2586–97. https://doi.org/10.1172/jci90832CrossRefPubMedPubMedCentral

10.

Polimeni M, Gulino GR, Gazzano E, Kopecka J, Marucco A, Fenoglio I, Cesano F, Campagnolo L, Magrini A, Pietroiusti A, Ghigo D, Aldieri E. Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-β-mediated Akt/GSK-3β/SNAIL-1 signalling pathway. Part Fibre Toxicol. 2016;13(1):27. https://doi.org/10.1186/s12989-016-0138-4CrossRefPubMedPubMedCentral

11.

Ryter SW, Rosas IO, Owen CA, Martinez FJ, Choi ME, Lee CG, Elias JA, Choi AMK. Mitochondrial dysfunction as a pathogenic mediator of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. Annals Am Thorac Soc. 2018;15(Suppl 4):S266–72. https://doi.org/10.1513/AnnalsATS.201808-585MGCrossRef

12.

Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166(5):1321–32. https://doi.org/10.1016/s0002-9440(10)62351-6CrossRefPubMedPubMedCentral

13.

Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: a recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol. 2022;237(1):59–85. https://doi.org/10.1002/jcp.30529CrossRefPubMed

14.

Hettiarachchi SU, Li YH, Roy J, Zhang F, Puchulu-Campanella E, Lindeman SD, Srinivasarao M, Tsoyi K, Liang X, Ayaub EA, Nickerson-Nutter C, Rosas IO, Low PS. Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models. Sci Transl Med. 2020;12(567). https://doi.org/10.1126/scitranslmed.aay3724

15.

Wang J, Hu K, Cai X, Yang B, He Q, Wang J, Weng Q. Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis. Acta Pharm Sinica B. 2022;12(1):18–32. https://doi.org/10.1016/j.apsb.2021.07.023CrossRef

16.

Song L, Zhang H, Hu M, Liu C, Zhao Y, Zhang S, Liu D. Sinomenine inhibits hypoxia induced breast cancer side population cells metastasis by PI3K/Akt/mTOR pathway. Bioorg Med Chem. 2021;31:115986. https://doi.org/10.1016/j.bmc.2020.115986CrossRefPubMed

17.

Xu F, Li Q, Wang Z, Cao X, Biomedicine. Pharmacotherapy = Biomedecine Pharmacotherapie. 2019;112:108592. https://doi.org/10.1016/j.biopha.2019.01.053CrossRefPubMed

18.

Zheng X, Li W, Xu H, Liu J, Ren L, Yang Y, Li S, Wang J, Ji T, Du G. Sinomenine ester derivative inhibits glioblastoma by inducing mitochondria-dependent apoptosis and autophagy by PI3K/AKT/mTOR and AMPK/mTOR pathway. Acta Pharm Sinica B. 2021;11(11):3465–80. https://doi.org/10.1016/j.apsb.2021.05.027CrossRef

19.

Fan H, Tu T, Zhang X, Yang Q, Liu G, Zhang T, Bao Y, Lu Y, Dong Z, Dong J, Zhao P. Sinomenine attenuates alcohol-induced acute liver injury via inhibiting oxidative stress, inflammation and apoptosis in mice. Food Chem Toxicology: Int J Published Br Industrial Biol Res Association. 2022;159:112759. https://doi.org/10.1016/j.fct.2021.112759CrossRef

20.

Chen H, Wang Y, Jiao FZ, Yang F, Li X, Wang LW. Sinomenine attenuates Acetaminophen-Induced Acute Liver Injury by decreasing oxidative stress and inflammatory response via regulating TGF-β/Smad Pathway in vitro and in vivo. Drug Des Devel Ther. 2020;14:2393–403. https://doi.org/10.2147/dddt.S248823CrossRefPubMedPubMedCentral

21.

Işık S, Karaman M, Micili S, Çağlayan-Sözmen Ş, Bağrıyanık HA, Arıkan-Ayyıldız Z, Uzuner N, Karaman Ö. Sinomenine ameliorates the airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in a murine model of chronic asthma. Allergol Immunopathol. 2018;46(1):67–75. https://doi.org/10.1016/j.aller.2017.05.004CrossRef

22.

Li Y, Zeng Z, Li Y, Huang W, Zhou M, Zhang X, Jiang W. Angiotensin-converting enzyme inhibition attenuates lipopolysaccharide-induced lung injury by regulating the balance between angiotensin-converting enzyme and angiotensin-converting enzyme 2 and inhibiting mitogen-activated protein kinase activation. Shock (Augusta Ga). 2015;43(4):395–404. https://doi.org/10.1097/shk.0000000000000302CrossRefPubMed

23.

Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988;41(4):467–70. https://doi.org/10.1136/jcp.41.4.467CrossRefPubMedPubMedCentral

24.

Li Q, Peng W, Zhang Z, Pei X, Sun Z, Ou Y. A phycocyanin derived eicosapeptide attenuates lung fibrosis development. Eur J Pharmacol. 2021;908:174356. https://doi.org/10.1016/j.ejphar.2021.174356CrossRefPubMed

25.

Liu B, Li R, Zhang J, Meng C, Zhang J, Song X, Lv C. MicroRNA-708-3p as a potential therapeutic target via the ADAM17-GATA/STAT3 axis in idiopathic pulmonary fibrosis. Exp Mol Med. 2018;50(3):e465. https://doi.org/10.1038/emm.2017.311CrossRefPubMedPubMedCentral

26.

Sheng H, Lin G, Zhao S, Li W, Zhang Z, Zhang W, Yun L, Yan X, Hu H. Antifibrotic Mechanism of Piceatannol in Bleomycin-Induced Pulmonary Fibrosis in mice. Front Pharmacol. 2022;13:771031. https://doi.org/10.3389/fphar.2022.771031CrossRefPubMedPubMedCentral

27.

Andugulapati SB, Gourishetti K, Tirunavalli SK, Shaikh TB, Sistla R. Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems. Phytomedicine. 2020;78:153298. https://doi.org/10.1016/j.phymed.2020.153298CrossRefPubMedPubMedCentral

28.

Liu W, Zhang Y, Zhu W, Ma C, Ruan J, Long H, Wang Y. Sinomenine inhibits the progression of rheumatoid arthritis by regulating the secretion of inflammatory cytokines and Monocyte/Macrophage subsets. Front Immunol. 2018;9:2228. https://doi.org/10.3389/fimmu.2018.02228CrossRefPubMedPubMedCentral

29.

Yamasaki H. Pharmacology of sinomenine, an anti-rheumatic alkaloid from Sinomenium Acutum. Acta Med Okayama. 1976;30(1):1–20.PubMed

30.

Tong B, Yu J, Wang T, Dou Y, Wu X, Kong L, Dai Y, Xia Y. Sinomenine suppresses collagen-induced arthritis by reciprocal modulation of regulatory T cells and Th17 cells in gut-associated lymphoid tissues. Mol Immunol. 2015;65(1):94–103. https://doi.org/10.1016/j.molimm.2015.01.014CrossRefPubMed

31.

Li RZ, Guan XX, Wang XR, Bao WQ, Lian LR, Choi SW, Zhang FY, Yan PY, Leung ELH, Pan HD, Liu L. Sinomenine hydrochloride bidirectionally inhibits progression of tumor and autoimmune diseases by regulating AMPK pathway. Phytomedicine. 2023;114:154751. https://doi.org/10.1016/j.phymed.2023.154751CrossRefPubMed

32.

Tzouvelekis A, Antoniou K, Kreuter M, Evison M, Blum TG, Poletti V, Grigoriu B, Vancheri C, Spagnolo P, Karampitsakos T, Bonella F, Wells A, Raghu G, Molina-Molina M, Culver DA, Bendstrup E, Mogulkoc N, Elia S, Cadranel J, Bouros D. The DIAMORFOSIS (DIAgnosis and management of lung canceR and FibrOSIS) survey: international survey and call for consensus. ERJ open Res. 2021;7(1). https://doi.org/10.1183/23120541.00529-2020

33.

Karampitsakos T, Galaris A, Chrysikos S, Papaioannou O, Vamvakaris I, Barbayianni I, Kanellopoulou P, Grammenoudi S, Anagnostopoulos N, Stratakos G, Katsaras M, Sampsonas F, Dimakou K, Manali ED, Papiris S, Tourki B, Juan-Guardela BM, Bakakos P, Bouros D, Herazo-Maya JD, Aidinis V, Tzouvelekis A. Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis. Respir Res. 2023;24(1):279. https://doi.org/10.1186/s12931-023-02551-xCrossRefPubMedPubMedCentral

34.

Karampitsakos T, Spagnolo P, Mogulkoc N, Wuyts WA, Tomassetti S, Bendstrup E, Molina-Molina M, Manali ED, Unat ÖS, Bonella F, Kahn N, Kolilekas L, Rosi E, Gori L, Ravaglia C, Poletti V, Daniil Z, Prior TS, Papanikolaou IC, Aso S, Tryfon S, Papakosta D, Tzilas V, Balestro E, Papiris S, Antoniou K, Bouros D, Wells A, Kreuter M, Tzouvelekis A. Lung cancer in patients with idiopathic pulmonary fibrosis: a retrospective multicentre study in Europe. Respirol (Carlton Vic). 2023;28(1):56–65. https://doi.org/10.1111/resp.14363CrossRef

35.

Khoubai FZ, Grosset CF. DUSP9, a dual-specificity phosphatase with a Key Role in Cell Biology and Human diseases. Int J Mol Sci. 2021;22(21). https://doi.org/10.3390/ijms222111538

36.

Xylourgidis N, Min K, Ahangari F, Yu G, Herazo-Maya JD, Karampitsakos T, Aidinis V, Binzenhöfer L, Bouros D, Bennett AM, Kaminski N, Tzouvelekis A. Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2019;317(5):L678–89. https://doi.org/10.1152/ajplung.00264.2018CrossRefPubMedPubMedCentral

37.

Pardo A, Cabrera S, Maldonado M, Selman M. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respir Res. 2016;17:23. https://doi.org/10.1186/s12931-016-0343-6CrossRefPubMedPubMedCentral

38.

Li XH, Xiao T, Yang JH, Qin Y, Gao JJ, Liu HJ, Zhou HG. Parthenolide attenuated bleomycin-induced pulmonary fibrosis via the NF-κB/Snail signaling pathway. Respir Res. 2018;19(1):111. https://doi.org/10.1186/s12931-018-0806-zCrossRefPubMedPubMedCentral

39.

Darby IA, Zakuan N, Billet F, Desmoulière A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci. 2016;73(6):1145–57. https://doi.org/10.1007/s00018-015-2110-0CrossRefPubMed

40.

Bormann T, Maus R, Stolper J, Tort Tarrés M, Brandenberger C, Wedekind D, Jonigk D, Welte T, Gauldie J, Kolb M, Maus UA. Role of matrix metalloprotease-2 and MMP-9 in experimental lung fibrosis in mice. Respir Res. 2022;23(1):180. https://doi.org/10.1186/s12931-022-02105-7CrossRefPubMedPubMedCentral

41.

Houghton AM. Matrix metalloproteinases in destructive lung disease. Matrix Biology: J Int Soc Matrix Biology. 2015;44. https://doi.org/10.1016/j.matbio.2015.02.002. 46:167 – 74.

42.

Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol. 2011;73:413–35. https://doi.org/10.1146/annurev-physiol-012110-142225CrossRefPubMed

43.

Herrera J, Henke CA, Bitterman PB. Extracellular matrix as a driver of progressive fibrosis. J Clin Investig. 2018;128(1):45–53. https://doi.org/10.1172/jci93557CrossRefPubMedPubMedCentral

44.

Kang H. Role of MicroRNAs in TGF-β signaling pathway-mediated pulmonary fibrosis. Int J Mol Sci. 2017;18(12). https://doi.org/10.3390/ijms18122527

45.

Yun SM, Kim SH, Kim EH. The molecular mechanism of transforming growth Factor-β signaling for intestinal fibrosis: a Mini-review. Front Pharmacol. 2019;10:162. https://doi.org/10.3389/fphar.2019.00162CrossRefPubMedPubMedCentral

46.

Fang L, Chen H, Kong R, Que J. Endogenous tryptophan metabolite 5-Methoxytryptophan inhibits pulmonary fibrosis by downregulating the TGF-β/SMAD3 and PI3K/AKT signaling pathway. Life Sci. 2020;260:118399. https://doi.org/10.1016/j.lfs.2020.118399CrossRefPubMed

47.

Lu Y, Zhang Y, Pan Z, Yang C, Chen L, Wang Y, Xu D, Xia H, Wang S, Chen S, Hao YJ, Sun G. Potential therapeutic effects of Tocotrienol-Rich Fraction (TRF) and Carotene Against Bleomycin-Induced Pulmonary fibrosis in rats via TGF-β/Smad, PI3K/Akt/mTOR and NF-κB signaling pathways. Nutrients. 2022;14(5). https://doi.org/10.3390/nu14051094

48.

Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386(2):157–71. https://doi.org/10.1056/NEJMra2032506CrossRefPubMed

49.

Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27(8):1345–56. https://doi.org/10.1038/s41591-021-01450-2CrossRefPubMed

50.

Karampitsakos T, Juan-Guardela BM, Tzouvelekis A, Herazo-Maya JD. Precision medicine advances in idiopathic pulmonary fibrosis. EBioMedicine. 2023;95:104766. https://doi.org/10.1016/j.ebiom.2023.104766CrossRefPubMedPubMedCentral

Title: Sinomenine attenuates pulmonary fibrosis by downregulating TGF-β1/Smad3, PI3K/Akt and NF-κB signaling pathways
Authors: Fuqiang Yao
Minghao Xu
Lingjun Dong
Xiao Shen
Yujie Shen
Yisheng Jiang
Ting Zhu
Chu Zhang
Guangmao Yu
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Idiopathic Pulmonary Fibrosis
Published in: BMC Pulmonary Medicine / Issue 1/2024
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-024-03050-5

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2024

Respiratory Rate Oxygenation (ROX) index as predictor of high flow nasal cannula in pediatric patients in pediatric intensive care unit

Variations in respiratory and functional symptoms at four months after hospitalisation due to COVID-19: a cross-sectional study

Implications of GCLC in prognosis and immunity of lung adenocarcinoma and multi-omics regulation mechanisms

Fractional exhaled nitric oxide in idiopathic pulmonary arterial hypertension and mixed connective tissue disease complicating pulmonary hypertension

Incidence and characteristics of aspiration pneumonia in the Nagasaki Prefecture from 2005 to 2019

Can an educational intervention in the context of inpatient pulmonary rehabilitation improve asthma self-management at work? A study protocol of a randomized controlled trial

Keynote webinar | Spotlight on medication adherence

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

At a glance: The STEP trials