Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies)

Pulmonary fibrosis develops both spontaneously and as a result of lung damage by radiotherapy and chemotherapy, infectious diseases, and inhalation of harmful substances and particulate matter. In this case, normal tissue repair is disturbed: instead of regeneration of normal lung cells, the damaged tissue is replaced by fibrotic one consisting of dense collagen fibers. This leads to loss of lung tissue elasticity and impairment of its function, which significantly reduces the quality of patients’ lives. The search for drugs for interstitial fibrotic lung diseases remains an urgent task, since the existing antifibrotic drugs only slow down disease progression and have side effects that significantly reduce the patients’ quality of life. It is believed that natural polyphenolic substances, in particular flavonoids, can be used for the treatment of pulmonary fibrosis. Flavonoids present in various fruits, vegetables, tea and wine show a wide range of biological activities. They have antioxidant, anti-inflammatory and immunomodulatory properties, making them promising for the treatment of various diseases, including pulmonary fibrosis. Some studies have shown that flavonoids can inhibit myofibroblast activation and collagen production, which is directly related to the fibrotic process. Flavonoids are safe and can influence the hallmarks of fibrosis: oxidative stress, inflammation, cell proliferation and differentiation. To date, a large amount of experimental data confirming the antifibrotic effect of flavonoids has been accumulated. In recent years, clinical studies have been conducted to investigate the efficacy and safety of flavonoids in patients with pulmonary fibrosis. For example, quercetin and curcumin are being explored and have shown encouraging results in reducing markers of inflammation and fibrosis in the lung. However, the main obstacle to the widespread introduction of flavonoid substances into clinical practice remains their low oral bioavailability and rapid metabolism. The experimental data on the effect of flavonoids on the development of pulmonary fibrosis is analyzed in this review. The perspectives for improving their bioavailability using modern delivery systems (nanoparticles, liposomes, etc.), as well as dosage forms for topical application, are discussed in this paperwork.

1. Wijsenbeek M, Cottin V. Spectrum of Fibrotic Lung Diseases. N Engl J Med. 2020 Sep 3;383(10):958–968. https://doi.org/10.1056/nejmra2005230

2. Dygai AM, Skurikhin EG, Krupin VA. Pulmonary fibrosis and stem cells: new treatment approaches. Moscow: Publishing House of the Russian Academy of Sciences, 2018, 200 p. (In Russ.).

3. Zheng Q, Cox IA, Campbell JA, Xia Q, Otahal P, de Graaff B, et al. Mortality and survival in idiopathic pulmonary fibrosis: a systematic review and meta-analysis. ERJ Open Res. 2022 Jan;8(1):00591–2021. https://doi.org/10.1183/23120541.00591-2021

4. Thong L, McElduff EJ, Henry MT. Trials and Treatments: An Update on Pharmacotherapy for Idiopathic Pulmonary Fibrosis. Life (Basel). 2023 Feb 10;13(2):486. https://doi.org/10.3390/LIFE13020486

5. Kato M, Sasaki S, Tateyama M, Arai Y, Motomura H, Sumiyoshi I, et al. Clinical Significance of Continuable Treatment with Nintedanib Over 12 Months for Idiopathic Pulmonary Fibrosis in a Real-World Setting. Drug Des Devel Ther. 2021;15:223–230. https://doi.org/10.2147/DDDT.S284819

6. Zhou F, Gu K, Zhou Y. Flavonoid intake is associated with lower all-cause and disease-specific mortality: The National Health and Nutrition Examination Survey 2007-2010 and 2017-2018. Front Nutr. 2023;10:1046998. https://doi.org/10.3389/fnut.2023.1046998

7. Zverev YF, Rykunova AY. Modern Nanocarriers as a Factor in Increasing the Bioavailability and Pharmacological Activity of Flavonoids. Appl Biochem Microbiol. 2022;58(9):1002–1020. https://doi.org/10.1134/S0003683822090149

8. Golubev AG, Gubareva EA, Anisimov VN, Fedoros EI. Polyphenols of natural origin against age-related disorders of tissue homeostasis. Advances in Gerontology. 2023;36(4):555–568. (In Russ.). https://doi.org/10.34922/AE.2023.36.4.014, EDN: UKTAJY

9. Chapman HA, Wei Y, Montas G, Leong D, Golden JA, Trinh BN, et al. Reversal of TGFβ1-Driven Profibrotic State in Patients with Pulmonary Fibrosis. N Engl J Med. 2020 Mar 12;382(11):1068–1070. https://doi.org/10.1056/NEJMC1915189

10. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554–563. https://doi.org/10.1016/j.ebiom.2018.12.052

11. Avdeev SN, Chikina SYu, Tyurin IE, Belevskiy AS, Terpigorev SA, Anan’yeva LP, et al. Chronic fibrosing progressing interstitial lung disease: a decision of Multidisciplinary Expert Board. Pulmonologiya. 2021;31(4):505–510. (In Russ.). https://doi.org/10.18093/0869-0189-2021-31-4-505-510, EDN: OKQQCQ

12. Sauleda J, Núñez B, Sala E, Soriano JB. Idiopathic Pulmonary Fibrosis: Epidemiology, Natural History, Phenotypes. Med Sci (Basel). 2018 Nov 29;6(4):110. https://doi.org/10.3390/MEDSCI6040110

13. Maher TM, Bendstrup E, Dron L, Langley J, Smith G, Khalid JM, et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021 Jul 7;22(1):197. https://doi.org/10.1186/S12931-021-01791-Z

14. Olson AL, Patnaik P, Hartmann N, Bohn RL, Garry EM, Wallace L. Prevalence and Incidence of Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype in the United States Estimated in a Large Claims Database Analysis. Adv Ther. 2021 Jul;38(7):4100–4114. https://doi.org/10.1007/s12325-021-01786-8

15. Duong-Quy S, Vo-Pham-Minh T, Tran-Xuan Q, Huynh-Anh T, Vo-Van T, Vu-Tran-Thien Q, et al. Post-COVID-19 Pulmonary Fibrosis: Facts-Challenges and Futures: A Narrative Review. Pulm Ther. 2023 Sep;9(3):295–307. https://doi.org/10.1007/s41030-023-00226-y

16. Parimon T, Yao C, Stripp BR, Noble PW, Chen P. Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pul- monary Fibrosis. Int J Mol Sci. 2020 Mar 25;21(7):2269. https://doi.org/10.3390/IJMS21072269

17. Hung C. Origin of Myofibroblasts in Lung Fibrosis. Curr Tissue Microenviron Rep. 2020 Dec 1;1(4):155–162. https://doi.org/10.1007/s43152-020-00022-9

18. Hinz B, Lagares D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol. 2020 Jan;16(1):11–31. https://doi.org/10.1038/s41584-019-0324-5

19. Miles T, Hoyne GF, Knight DA, Fear MW, Mutsaers SE, Prêle CM. The contribution of animal models to understanding the role of the immune system in human idiopathic pulmonary fibrosis. Clin Transl Immunology. 2020;9(7):e1153. https://doi.org/10.1002/CTI2.1153

20. Liu T, De Los Santos FG, Phan SH. The Bleomycin Model of Pulmonary Fibrosis. Methods Mol Biol. 2017;1627:27–42. https://doi.org/10.1007/978-1-4939-7113-8_2

21. Confalonieri P, Volpe MC, Jacob J, Maiocchi S, Salton F, Ruaro B, et al. Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Cells. 2022 Jun 30;11(13):2095. https://doi.org/10.3390/CELLS11132095

22. 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 Feb;65:56–69. https://doi.org/10.1016/J.MAM.2018.08.004

23. Parimon T, Yao C, Habiel DM, Ge L, Bora SA, Brauer R, et al. Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles. JCI Insight. 2019 Aug 8;5(17):e129359. https://doi.org/10.1172/jci.insight.129359

24. Herrera J, Henke CA, Bitterman PB. Extracellular matrix as a driver of progressive fibrosis. J Clin Invest. 2018 Jan 2;128(1):45–53. https://doi.org/10.1172/JCI93557

25. Selman M, Pardo A. Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology. Ageing Res Rev. 2021 Sep;70:101393. https://doi.org/https://doi.org/10.1016/j.arr.2021.101393

26. Mebratu YA, Soni S, Rosas L, Rojas M, Horowitz JC, Nho R. The aged extracellular matrix and the profibrotic role of senes-cence-associated secretory phenotype. Am J Physiol Cell Physiol. 2023 Sep 1;325(3):C565–C579. https://doi.org/10.1152/AJPCELL.00124.2023

27. Shochet G, Bardenstein-Wald B, McElroy M, Kukuy A, Surber M, Edelstein E, et al. Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis. Int J Mol Sci. 2021 Mar 24;22(7):3331. https://doi.org/10.3390/ijms22073331

28. Saito S, Alkhatib A, Kolls JK, Kondoh Y, Lasky JA. Pharmacotherapy and adjunctive treatment for idiopathic pulmonary fibrosis (IPF). J Thorac Dis. 2019 Sep;11(Suppl 14):S1740–S1754. https://doi.org/10.21037/jtd.2019.04.62

29. Petnak T, Lertjitbanjong P, Thongprayoon C, Moua T. Impact of Antifibrotic Therapy on Mortality and Acute Exacerbation in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Chest. 2021 Nov;160(5):1751–1763. https://doi.org/10.1016/J.CHEST.2021.06.049

30. Pitre T, Mah J, Helmeczi W, Khalid MF, Cui S, Zhang M, et al. Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis. Thorax. 2022 Dec;77(12):1243–1250. https://doi.org/10.1136/THORAXJNL-2021-217976

31. Wei Y, Dong W, Jackson J, Ho TC, Le Saux CJ, Brumwell A, et al. Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021 Jul;76(7):729–732. https://doi.org/10.1136/THORAXJNL-2020-215745

32. Moore BB, Lawson WE, Oury TD, Sisson TH, Raghavendran K, Hogaboam CM. Animal models of fibrotic lung disease. Am J Respir Cell Mol Biol. 2013 Aug;49(2):167–117. https://doi.org/10.1165/RCMB.2013-0094TR

33. Gul A, Yang F, Xie C, Du W, Mohammadtursun N, Wang B, et al. Pulmonary fibrosis model of mice induced by different administration methods of bleomycin. BMC Pulm Med. 2023 Mar 21;23(1):91. https://doi.org/10.1186/s12890-023-02349-z

34. Boots AW, Veith C, Albrecht C, Bartholome R, Drittij MJ, Claessen SMH, et al. The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice. BMC Pulm Med. 2020 Apr 29;20(1):112. https://doi.org/10.1186/S12890-020-1142-X

35. Mehrzadi S, Hosseini P, Mehrabani M, Siahpoosh A, Goudarzi M, Khalili H, et al. Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats by Combination Treatment of Two Natural Phenolic Compounds: Quercetin and Gallic Acid. Nutr Cancer. 2021;73(10):2039–2049. https://doi.org/10.1080/01635581.2020.1820053

36. Liu H, Bai X, Wei W, Li Z, Zhang Z, Tan W, et al. Calycosin Ameliorates Bleomycin-Induced Pulmonary Fibrosis via Suppressing Oxidative Stress, Apoptosis, and Enhancing Autophagy. Evid Based Complement Alternat Med. 2022;2022:9969729. https://doi.org/10.1155/2022/9969729

37. 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. 2019 Jan;43(1):117–126. https://doi.org/10.3892/IJMM.2018.3965

38. 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 Nov;78:153298. https://doi.org/10.1016/J.PHYMED.2020.153298

39. Xiao T, Wei Y, Cui M, Li X, Ruan H, Zhang L, et al. Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis. Phytomedicine. 2021 Oct;91:153704. https://doi.org/10.1016/J.PHYMED.2021.153704

40. Sun SC, Han R, Hou SS, Yi HQ, Chi SJ, Zhang AH. Juglanin alleviates bleomycin-induced lung injury by suppressing inflammation and fibrosis via targeting sting signaling. Biomed Pharmacother. 2020 Jul;127:110119. https://doi.org/10.1016/J.BIOPHA.2020.110119

41. Ma C, Lyu M, Deng C, Liu X, Cui Y, Shen Y, et al. Cyanidin-3-galactoside ameliorates silica-induced pulmonary fibrosis by inhibiting fibroblast differentiation via Nrf2/p38/Akt/NOX4. Journal of Functional Foods. 2022 May 1;92:105034. https://doi.org/10.1016/j.jff.2022.105034

42. Zhou Z, Kandhare AD, Kandhare AA, Bodhankar SL. Hesperidin ameliorates bleomycin-induced experimental pulmonary fibrosis via inhibition of TGF-beta1/Smad3/AMPK and IkappaBalpha/NF-kappaB pathways. EXCLI J. 2019;18:723–745. https://doi.org/10.17179/excli2019-1094

43. Shariati S, Kalantar H, Pashmforoosh M, Mansouri E, Khodayar MJ. Epicatechin protective effects on bleomycin-induced pulmonary oxidative stress and fibrosis in mice. Biomed Pharmacother. 2019 Jun;114:108776. https://doi.org/10.1016/J.BIOPHA.2019.108776

44. Li S, Shao L, Fang J, Zhang J, Chen Y, Yeo AJ, et al. Hesperetin attenuates silica-induced lung injury by reducing oxidative damage and inflammatory response. Exp Ther Med. 2021 Apr;21(4):297. https://doi.org/10.3892/ETM.2021.9728

45. Zhao H, Li C, Li L, Liu J, Gao Y, Mu K, et al. Baicalin alleviates bleomycin induced pulmonary fibrosis and fibroblast proliferation in rats via the PI3K/AKT signaling pathway. Mol Med Rep. 2020 Jun;21(6):2321–2334. https://doi.org/10.3892/MMR.2020.11046

46. Yang Y, Jin X, Jiao X, Li J, Liang L, Ma Y, et al. Advances in Pharmacological Actions and Mechanisms of Flavonoids from Traditional Chinese Medicine in Treating Chronic Obstructive Pulmonary Disease. Evid Based Complement Alternat Med. 2020;2020:8871105. https://doi.org/10.1155/2020/8871105

47. Geng F, Xu M, Zhao L, Zhang H, Li J, Jin F, et al. Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence. Front Pharmacol. 2022;13:912029. https://doi.org/10.3389/fphar.2022.912029

48. Yuan L, Sun Y, Zhou N, Wu W, Zheng W, Wang Y. Dihydroquercetin Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting Ferroptosis Signaling Pathway. Front Pharmacol. 2022;13:845600. https://doi.org/10.3389/fphar.2022.845600

49. Cui Y, Zhao J, Chen J, Kong Y, Wang M, Ma Y, et al. Cyanidin-3-galactoside from Aronia melanocarpa ameliorates silica-induced pulmonary fibrosis by modulating the TGF-β/mTOR and NRF2/HO-1 pathways. Food Sci Nutr. 2022 Aug;10(8):2558–2567. https://doi.org/10.1002/FSN3.2861

50. Zhongyin Z, Wei W, Juan X, Guohua F. Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway. Oxid Med Cell Longev. 2022;2022:7291774. https://doi.org/10.1155/2022/7291774

51. Adamcakova J, Balentova S, Barosova R, Hanusrichterova J, Mikolka P, Prso K, et al. Effects of Green Tea Polyphenol Epigallocatechin-3-Gallate on Markers of Inflammation and Fibrosis in a Rat Model of Pulmonary Silicosis. Int J Mol Sci. 2023 Jan 17;24(3):1857. https://doi.org/10.3390/ijms24031857

52. Wang L, Liu H, He Q, Gan C, Li Y, Zhang Q, et al. Galangin ameliorated pulmonary fibrosis in vivo and in vitro by regulating epithelial-mesenchymal transition. Bioorg Med Chem. 2020 Oct 1;28(19):115663. https://doi.org/10.1016/J.BMC.2020.115663

53. 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

54. Thilakarathna SH, Rupasinghe HPV. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients. 2013 Aug 28;5(9):3367–3387. https://doi.org/10.3390/NU5093367

55. Liu L, Tang Y, Gao C, Li Y, Chen S, Xiong T, et al. Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers. Colloids Surf B Biointerfaces. 2014 Mar 1;115:125–131. https://doi.org/10.1016/j.colsurfb.2013.11.029

56. Zhang J, Chao L, Liu X, Shi Y, Zhang C, Kong L, et al. The potential application of strategic released apigenin from polymeric carrier in pulmonary fibrosis. Exp Lung Res. 2017;43(9–10):359–369. https://doi.org/10.1080/01902148.2017.1380086

57. Xie X-F, Lu Y, Chen X-S, Muhetaer G, Tao H, Li H, Liu H-J. Inhalation therapy for pulmonary fibrosis: chemical medicines and herbal medicines. TMR Modern Herb Med. 2023;6(3):14. https://doi.org/10.53388/MHM2023014

58. Guan M, Shi R, Zheng Y, Zeng X, Fan W, Wang Y, et al. Characterization, in Vitro and in Vivo Evaluation of Naringenin-Hy- droxypropyl-ß-Cyclodextrin Inclusion for Pulmonary Delivery. Molecules. 2020 Jan 28;25(3):554. https://doi.org/10.3390/MOLECULES25030554

59. Ji P, Yu T, Liu Y, Jiang J, Xu J, Zhao Y, et al. Naringenin-loaded solid lipid nanoparticles: preparation, controlled delivery, cellular uptake, and pulmonary pharmacokinetics. Drug Des Devel Ther. 2016;10:911–925. https://doi.org/10.2147/DDDT.S97738

60. Yu Z, Liu X, Chen H, Zhu L. Naringenin-Loaded Dipalmitoylphosphatidylcholine Phytosome Dry Powders for Inhaled Treatment of Acute Lung Injury. J Aerosol Med Pulm Drug Deliv. 2020 Aug;33(4):194–204. https://doi.org/10.1089/jamp.2019.1569