Therapeutic Use of Fisetin and Pirfenidone Combination in Bleomycin-induced Pulmonary Fibrosis in Adult Male Albino Rats

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2024 Aug 20

PMID 39162796

Authors

Aysegul Burcin Yildirim

Mehmet Gol

Akin Yigin

Leyla Cimen

Hikmet Dinc

Hamit Yildiz

Begum Kayar

Affiliations

Soon will be listed here.

Abstract

Pulmonary fibrosis is an important health problem; one of the drugs used in its treatment is pirfenidone (PFD). Fisetin (FST) is a flavonoid with antioxidative, anti-inflammatory, and antifibrotic effects. The aim of this study was to induce PF in rats with bleomycin (BLM) and to investigate the combined effect of PFD and FST in the treatment of fibrosis. In the study, 40 male Wistar rats were divided into five groups (n = 8). Sham group was administered saline on day 0 and BLM (5 mg/kg, i.t.) was administered to the other groups; BLM + PFD group: PFD (50 mg/kg) was administered every day between the first and 15th days; BLM + FST group: FST (25 mg/kg) was administered between the first and 15th days; BLM + PFD + FST group: PFD (50 mg/kg) and FST (25 mg/kg) were administered by gavage every day between the first and 15th days. At the end of the 15th day, BAL was performed under anaesthesia and lung tissues were removed. Histopathological, biochemical, and RT-PCR analyses were performed in the lung tissue. In our study, the concomitant use of FST and PFD caused downregulation of NF-κB p65, TGF-β1, and α-SMA expressions; downregulation of TIMP-1, MMP-2, and MMP-9 genes; downregulation of HYP, MPO, and MDA activity; decrease in the number of differential cells in BAL; and upregulation of GSH. This shows that FST and PFD have antifibrotic, antioxidative, and anti-inflammatory effects. Our results show that the combined use of PFD and FST in BLM-induced pulmonary fibrosis reduces extracellular matrix accumulation, downregulates the level of gelatinases and their inhibitors, and provides significant improvements in antioxidative defence parameters.

Citing Articles

From micro to macro, nanotechnology demystifies acute pancreatitis: a new generation of treatment options emerges.

Du W, Wang X, Zhou Y, Wu W, Huang H, Jin Z J Nanobiotechnology. 2025; 23(1):57.

PMID: 39881355 PMC: 11776322. DOI: 10.1186/s12951-025-03106-6.

References

Bassiouni W, Ali M, Schulz R . Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J. 2021; 288(24):7162-7182. DOI: 10.1111/febs.15701. View

Brenner D, Kisseleva T, Scholten D, Paik Y, Iwaisako K, Inokuchi S . Origin of myofibroblasts in liver fibrosis. Fibrogenesis Tissue Repair. 2012; 5(Suppl 1):S17. PMC: 3368775. DOI: 10.1186/1755-1536-5-S1-S17. View

Chen J, Tipoe G, Liong E, So H, Leung K, Tom W . Green tea polyphenols prevent toxin-induced hepatotoxicity in mice by down-regulating inducible nitric oxide-derived prooxidants. Am J Clin Nutr. 2004; 80(3):742-51. DOI: 10.1093/ajcn/80.3.742. View

Chitra P, Saiprasad G, Manikandan R, Sudhandiran G . Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-κB dependant TGF-β activation: a biphasic experimental study. Toxicol Lett. 2013; 219(2):178-93. DOI: 10.1016/j.toxlet.2013.03.009. View

Chou R, Hsieh S, Yu Y, Huang M, Huang Y, Hsieh Y . Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PLoS One. 2013; 8(8):e71983. PMC: 3733924. DOI: 10.1371/journal.pone.0071983. View

Corbel M, Lanchou J, Germain N, Malledant Y, Boichot E, Lagente V . Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice. Eur J Pharmacol. 2001; 426(1-2):113-21. DOI: 10.1016/s0014-2999(01)01209-2. View

Cortijo J, Cerda-Nicolas M, Serrano A, Bioque G, Estrela J, Santangelo F . Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats. Eur Respir J. 2001; 17(6):1228-35. DOI: 10.1183/09031936.01.00049701. View

Di Sario A, Bendia E, Macarri G, Candelaresi C, Taffetani S, Marzioni M . The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2. Dig Liver Dis. 2004; 36(11):744-51. DOI: 10.1016/j.dld.2004.05.012. View

El-Khouly D, El-Bakly W, Awad A, El-Mesallamy H, El-Demerdash E . Thymoquinone blocks lung injury and fibrosis by attenuating bleomycin-induced oxidative stress and activation of nuclear factor Kappa-B in rats. Toxicology. 2012; 302(2-3):106-13. DOI: 10.1016/j.tox.2012.09.001. View

10.

Evans R, Tian Y, Steadman R, Phillips A . TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins. Exp Cell Res. 2003; 282(2):90-100. DOI: 10.1016/s0014-4827(02)00015-0. View

11.

Goh F, Upton N, Guan S, Cheng C, Shanmugam M, Sethi G . Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB. Eur J Pharmacol. 2012; 679(1-3):109-16. DOI: 10.1016/j.ejphar.2012.01.002. View

12.

Guo J, Yang Z, Jia Q, Bo C, Shao H, Zhang Z . Pirfenidone inhibits epithelial-mesenchymal transition and pulmonary fibrosis in the rat silicosis model. Toxicol Lett. 2018; 300:59-66. DOI: 10.1016/j.toxlet.2018.10.019. View

13.

Gupta S, Tyagi A, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal B . Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys. 2014; 559:91-9. DOI: 10.1016/j.abb.2014.06.006. View

14.

Hada Y, Uchida H, Wada J . Fisetin Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Macrophage. Biomed Res Int. 2021; 2021:5570885. PMC: 8057890. DOI: 10.1155/2021/5570885. View

15.

Hagiwara S, Ishii Y, Kitamura S . Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med. 2000; 162(1):225-31. DOI: 10.1164/ajrccm.162.1.9903129. View

16.

Hosseini S, Imenshahidi M, Hosseinzadeh H, Karimi G . Effects of plant extracts and bioactive compounds on attenuation of bleomycin-induced pulmonary fibrosis. Biomed Pharmacother. 2018; 107:1454-1465. DOI: 10.1016/j.biopha.2018.08.111. View

17.

Inomata M, Kamio K, Azuma A, Matsuda K, Kokuho N, Miura Y . Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res. 2014; 15:16. PMC: 3930125. DOI: 10.1186/1465-9921-15-16. View

18.

Gisli Jenkins R, Moore B, Chambers R, Eickelberg O, Konigshoff M, Kolb M . An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2017; 56(5):667-679. PMC: 5800895. DOI: 10.1165/rcmb.2017-0096ST. View

19.

Kalantar H, Sadeghi E, Abolnezhadian F, Goudarzi M, Hemmati A, Basir Z . Carnosol attenuates bleomycin-induced lung damage via suppressing fibrosis, oxidative stress and inflammation in rats. Life Sci. 2021; 287:120059. DOI: 10.1016/j.lfs.2021.120059. View

20.

Kim T, Kim S, Seo J, Chung H, Kwak H, Lee S . Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosis. Tohoku J Exp Med. 2011; 223(1):45-54. DOI: 10.1620/tjem.223.45. View