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Effects of pirfenidone, vitamin E, and pirfenidone–vitamin E combination in paraquat-induced pulmonary fibrosis

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Abstract

Paraquat-induced pulmonary fibrosis is a progressive and fatal interstitial lung disease, a condition for that, there is no effective treatment and its prognosis is appalling. Since multiple coactivated pathways are involved, targeting these pathways using combination regimens is plausible for successful therapy. So, the aim of the present study was to evaluate the therapeutic efficacy of pirfenidone–vitamin E combination therapy in (paraquat) PQ-induced lung fibrosis model. After the development of PQ-induced lung fibrosis, pirfenidone, vitamin E, pirfenidone plus vitamin E, and water (as a vehicle) were orally administered for 14 consecutive days (From day 14 to day 28). The comparison of efficacies was performed by evaluating histopathology changes, hydroxyproline content, and oxidative stress. Either pirfenidone or vitamin E solely could recover the pathological changes of paraquat, decreased lipid peroxidation, and restored the antioxidant enzymes towards normal values. Hydroxyproline content was significantly reduced by both pirfenidone and vitamin E administration. Concurrent treatment with pirfenidone and vitamin E intensified all of these therapeutics effects indicating more potent antifibrotic and anti-inflammatory impacts. Therefore, pirfenidone plus vitamin E offers potential as a combination therapy for the treatment of paraquat-induced pulmonary fibrosis.

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Abbreviations

Paraquat:

(PubChem CID: 15938)

Pirfenidone:

(PubChem CID: 40632)

Vitamin E:

(PubChem CID: 14985)

Malondialdehyde:

(PubChem CID: 10964)

Hydroxyproline :

(PubChem CID: 5810)

PF:

Pirfenidone

PQ:

Paraquat

CAT:

Catalase

SOD:

Super oxide dismutase

MDA:

Malondialdehyde

HP:

Hydroxyproline

References

  • Aebi H (1984) [13] Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  Google Scholar 

  • Ashcroft T, Simpson JM, Timbrell V (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 41:467–470

    Article  CAS  Google Scholar 

  • Bese N et al (2007) Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. Clin Oncol 19:260–264

    Article  CAS  Google Scholar 

  • Beyer WF, Fridovich I (1987) Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions. Anal Biochem 161:559–566

    Article  CAS  Google Scholar 

  • Bus JS, Gibson JE (1984) Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect 55:37

    Article  CAS  Google Scholar 

  • Card JW, Racz WJ, Brien JF, Massey TE (2003) Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-β1 gene expression but not prevention of mitochondrial dysfunction. J Pharmacol Exp Ther 304:277–283

    Article  CAS  Google Scholar 

  • Cherniack RM, Colby TV, Flint A, Thurlbeck WM, Waldron J, Ackerson L, King TE Jr (1991) Quantitative assessment of lung pathology in idiopathic pulmonary fibrosis. The BAL Cooperative Group Steering Committee. Am Rev Respir Dis 144:892–900. https://doi.org/10.1164/ajrccm/144.4.892

    Article  CAS  PubMed  Google Scholar 

  • Day BJ (2008) Antioxidants as potential therapeutics for lung fibrosis. Antioxid Redox Signal 10:355–370

    Article  CAS  Google Scholar 

  • Deger Y, Yur F, Ertekin A, Mert N, Dede S, Mert H (2007) Protective effect of α-tocopherol on oxidative stress in experimental pulmonary fibrosis in rats. Cell Biochem Funct 25:633–637

    Article  CAS  Google Scholar 

  • Devaraj S, Jialal I (2005) α-Tocopherol decreases tumor necrosis factor-α mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. Free Radic Biol Med 38:1212–1220

    Article  CAS  Google Scholar 

  • Dou T et al. (2015) Nrf2/ARE pathway involved in oxidative stress induced by paraquat in human neural progenitor cells. Oxidative medicine and cellular longevity 2016

  • Elenga N et al (2018) Clinical features and prognosis of paraquat poisoning in French Guiana: a review of 62 cases. Medicine 97

  • Fois AG et al (2018a) Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review. Respir Res 19:51

    Article  Google Scholar 

  • Fois AG et al (2018b) Antioxidant activity mediates pirfenidone antifibrotic effects in human pulmonary vascular smooth muscle cells exposed to sera of idiopathic pulmonary fibrosis patients. Oxidative Med Cell Longev:2018

  • Futamura Y (1996) Toxicity of amiodarone on mouse pulmonary endothelial cells cultured with or without alveolar macrophages. J Toxicol Sci 21:253–267

    Article  CAS  Google Scholar 

  • Gao F, Kinnula VL, Myllärniemi M, Oury TD (2008) Extracellular superoxide dismutase in pulmonary fibrosis. Antioxid Redox Signal 10:343–354

    Article  CAS  Google Scholar 

  • Gawarammana IB, Buckley NA (2011) Medical management of paraquat ingestion. Br J Clin Pharmacol 72:745–757. https://doi.org/10.1111/j.1365-2125.2011.04026.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghazi-Khansari M, Mohammadi-Karakani A, Sotoudeh M, Mokhtary P, Pour-Esmaeil E, Maghsoud S (2007) Antifibrotic effect of captopril and enalapril on paraquat-induced lung fibrosis in rats. J Appl Toxicol 27:342–349. https://doi.org/10.1002/jat.1212

    Article  CAS  PubMed  Google Scholar 

  • Hemmati A, Nazari Z, Ranjbari N, Torfi A (2008) Comparison of the preventive effect of vitamin C and E on hexavalent chromium induced pulmonary fibrosis in rat. Inflammopharmacology 16:195–197

    Article  CAS  Google Scholar 

  • Hubner RH et al (2008) Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 44(507-511):514–507. https://doi.org/10.2144/000112729

    Article  CAS  Google Scholar 

  • Iyer SN, Hyde DM, Giri SN (2000) Anti-inflammatory effect of pirfenidone in the bleomycin-hamster model of lung inflammation. Inflammation 24:477–491

    Article  CAS  Google Scholar 

  • Kachel D, Moyer T, Martin W (1990) Amiodarone-induced injury of human pulmonary artery endothelial cells: protection by alpha-tocopherol. J Pharmacol Exp Ther 254:1107–1112

    CAS  PubMed  Google Scholar 

  • Kalantar M, Khodayar MJ, Kalantari H, Khorsandi L, Hemmati AA (2018) Therapeutic effect of gallic acid against paraquat-induced lung injury in rat. Jundishapur J Nat Pharm Prod 13:13

    Google Scholar 

  • Kandhare AD, Mukherjee A, Ghosh P, Bodhankar SL (2016) Efficacy of antioxidant in idiopathic pulmonary fibrosis: a systematic review and meta-analysis. EXCLI J 15:636

    PubMed  PubMed Central  Google Scholar 

  • Kar S, Biswas S, Banerjee ER (2016) Evaluating the ameliorative potential of plant flavonoids and their nanocomposites in bleomycin induced idiopathic pulmonary fibrosis. Biomed Res Therapy 3:707–722

    Article  Google Scholar 

  • Li T, Yang X, Xin S, Cao Y, Wang N (2017) Paraquat poisoning induced pulmonary epithelial mesenchymal transition through Notch1 pathway. Sci Rep 7:924

    Article  Google Scholar 

  • Liu M-W et al (2016) Radix puerariae extracts ameliorate paraquat-induced pulmonary fibrosis by attenuating follistatin-like 1 and nuclear factor erythroid 2p45-related factor-2 signalling pathways through downregulation of miRNA-21 expression. BMC Complement Altern Med 16:1

    Google Scholar 

  • Oku H, Nakazato H, Horikawa T, Tsuruta Y, Suzuki R (2002) Pirfenidone suppresses tumor necrosis factor-α, enhances interleukin-10 and protects mice from endotoxic shock. Eur J Pharmacol 446:167–176

    Article  CAS  Google Scholar 

  • Oku H et al (2008) Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 590:400–408

    Article  CAS  Google Scholar 

  • Pourgholamhossein F et al (2016) Thymoquinone effectively alleviates lung fibrosis induced by paraquat herbicide through down-regulation of pro-fibrotic genes and inhibition of oxidative stress. Environ Toxicol Pharmacol 45:340–345. https://doi.org/10.1016/j.etap.2016.06.019

    Article  CAS  PubMed  Google Scholar 

  • Pourgholamhossein F et al (2018) Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. Food Chem Toxicol 112:39–46

    Article  CAS  Google Scholar 

  • Rasooli R, Pourgholamhosein F, Kamali Y, Nabipour F, Mandegary A (2018) Combination therapy with pirfenidone plus prednisolone ameliorates paraquat-induced pulmonary fibrosis. Inflammation 41:134–142. https://doi.org/10.1007/s10753-017-0671-9

    Article  CAS  PubMed  Google Scholar 

  • Reddy GK, Enwemeka CS (1996) A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem 29:225–229

    Article  CAS  Google Scholar 

  • Ruch RJ, Bandyopadhyay S, Somani P, Klaunig JE (1991) Evaluation of amiodarone free radical toxicity in rat hepatocytes. Toxicol Lett 56:117–126

    Article  CAS  Google Scholar 

  • Salazar-Montes A, Ruiz-Corro L, López-Reyes A, Castrejón-Gómez E, Armendáriz-Borunda J (2008) Potent antioxidant role of pirfenidone in experimental cirrhosis. Eur J Pharmacol 595:69–77

    Article  CAS  Google Scholar 

  • Schaefer C, Ruhrmund D, Pan L, Seiwert S, Kossen K (2011) Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 20:85–97

    Article  CAS  Google Scholar 

  • Seifirad S, Keshavarz A, Taslimi S, Aran S, Abbasi H, Ghaffari A (2012) Effect of pirfenidone on pulmonary fibrosis due to paraquat poisoning in rats. Clin Toxicol 50:754–758

    Article  CAS  Google Scholar 

  • Selvaggio AS, Noble PW (2016) Pirfenidone Initiates a New Era in the Treatment of Idiopathic Pulmonary Fibrosis. Annu Rev Med 67:487–495

    Article  CAS  Google Scholar 

  • Veith C, Boots AW, Idris M, van Schooten F-J, van der Vliet A (2019) Redox imbalance in idiopathic pulmonary fibrosis: a role for oxidant cross-talk between NADPH oxidase enzymes and mitochondria. Antioxid Redox Signal

  • Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S (2013) Evaluating the ameliorative potential of quercetin against the bleomycin-induced pulmonary fibrosis in wistar rats. Pulm Med:2013

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Funding

This study was funded by Kerman University of Medical Sciences (grant number 97000369).

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Correspondence to Ali Mandegary.

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Rasooli, R., Kamali, Y. & Mandegary, A. Effects of pirfenidone, vitamin E, and pirfenidone–vitamin E combination in paraquat-induced pulmonary fibrosis. Comp Clin Pathol 29, 667–673 (2020). https://doi.org/10.1007/s00580-020-03104-0

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