Effects of Sildenafil and Vitamin E on Paraquat-Induced Pulmonary Fibrosis in Rats

Document Type : Original Article

Authors

1 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

10.30476/tips.2024.103997.1255

Abstract

Paraquat, specifically concentrated in lung tissue, leads to lung damage through oxidative and inflammatory processes. Pulmonary fibrosis occurs due to inflammation and an imbalance in the antioxidant system. Drugs like sildenafil, which inhibits phosphodiesterase enzymes, are used to treat pulmonary arterial hypertension. Antioxidants such as vitamin E can restore the oxidant-antioxidant balance. This study aimed to evaluate the effects of sildenafil and vitamin E on paraquat-induced pulmonary fibrosis. Male Wistar rats were used in animal studies. Paraquat was administered orally (R1-1) at a single dose of 40 mg/kg to induce lung fibrosis. Three groups were studied: Sildenafil administered orally (10 mg/kg) for 14 days. Vitamin E administered orally (500 mg/kg) for 14 days. Simultaneous administration of vitamin E (500 mg/kg) and sildenafil (10 mg/kg) for 14 days. Biochemical and histopathological tests were performed and compared with a control group. Paraquat administration caused fibrosis and an oxidant-antioxidant imbalance in lung tissue. Treatment with sildenafil and vitamin E increased glutathione (total GSH) and superoxide dismutase (SOD) levels while decreasing malondialdehyde (MDA) and hydroxyproline (HYP) levels compared to the paraquat group. Tumor Necrosis Factor-α (TNF-α) showed no significant changes in the study group compared to the control group. Treatment with sildenafil and vitamin E improved the oxidant-antioxidant balance in lung tissue exposed to paraquat. Additionally, this study demonstrated significant antioxidant effects of sildenafil and vitamin E against paraquat-induced oxidative damage.

Highlights

Mohammad Javad Khoshnoud (Google Scholar)

Hossein Sadeghi (Google Scholar)

Keywords

References

1.    Mohammadi-Bardbori A, Ghazi-Khansari M. The inhibitory effect of captoperil on paraquat toxicity in mitochondria isolated from the rat liver. Toxicol  Lett. 2006(164):S246.
2.    Goldman SM, Kamel F, Ross GW, Bhudhikanok GS, Hoppin JA, Korell M, et al. Genetic modification of the association of paraquat and Parkinson's disease. Mov Disord. 2012 Nov;27(13):1652-8. doi: 10.1002/mds.25216. Epub 2012 Oct 8. PMID: 23045187; PMCID: PMC3572192.
3.    Chen J, Su Y, Lin F, Iqbal M, Mehmood K, Zhang H, Shi D. Effect of paraquat on cytotoxicity involved in oxidative stress and inflammatory reaction: A review of mechanisms and ecological implications. Ecotoxicol Environ Saf. 2021 Aug 26;224:112711. doi: 10.1016/j.ecoenv.2021.112711. Epub ahead of print. PMID: 34455184.
4.    Okorondu M, Okorondu S, Alisi C, EMEJULU A. Ameliorative effect of psidium guajava leaf extract on paraquat induced renal and reproductive hormone toxicity. Sci Res J. 2019;7:2201-796.
5.    Beheshti DH, Vakili P, Mousavi  FS, Ranji N. Epigenetic effects of paraquat on development of preimplantation embryo. J Plasma Biomarkers. 2022;15(3):79-96
6.    Ghazi-Khansari M, Mohammadi-Bardbori A. Captopril ameliorates toxicity induced by paraquat in mitochondria isolated from the rat liver. Toxicol In Vitro. 2007 Apr;21(3):403-7. doi: 10.1016/j.tiv.2006.10.001. Epub 2006 Oct 10. PMID: 17107770.
7.    Sadeghy R, Tabrizi BA, Fartashvand M. Evaluation of cardiac injury biomarkers in serum following concomitant administration of sildenafil citrate with dextromethorphan and chlorpheniramine in rat. J Vet Clin Pathol. 2021;14(56):fa401-fa10.
8.    Oudiz RJ, Roveran G, Hansen JE, Sun XG, Wasserman K. Effect of sildenafil on ventilatory efficiency and exercise tolerance in pulmonary hypertension. Eur J Heart Fail. 2007 Sep;9(9):917-21. doi: 10.1016/j.ejheart.2007.06.013. Epub 2007 Aug 16. PMID: 17707133; PMCID: PMC2071948.
9.    Karaarslan C. Ocular Side Effects of Sildenafil That Persist Beyond 24 h-A Case Series. Front Neurol. 2020 Feb 7;11:67. doi: 10.3389/fneur.2020.00067. PMID: 32117027; PMCID: PMC7019110.
10.    Yildirim A, Ersoy Y, Ercan F, Atukeren P, Gumustas K, Uslu U, Alican I. Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis. Pulm Pharmacol Ther. 2010 Jun;23(3):215-21. doi: 10.1016/j.pupt.2009.11.002. Epub 2009 Nov 27. PMID: 19945540.
11.    Yavari M, Mousavi SAJ, Janani L, Feizy Z, Vafa M. Effects of supplementation of vitamins D, C and E on Idiopathic Pulmonary Fibrosis (IPF): A clinical trial. Clin Nutr ESPEN. 2022 Jun;49:295-300. doi: 10.1016/j.clnesp.2022.03.035. Epub 2022 Apr 6. PMID: 35623829.
12.    Kaya V, Yazkan R, Yıldırım M, Doğuç DK, Süren D, Bozkurt KK, et al. The relation of radiation-induced pulmonary fibrosis with stress and the efficiency of antioxidant treatment: an experimental study. Med Sci Monit. 2014 Feb 21;20:290-6. doi: 10.12659/MSM.890334. PMID: 24556959; PMCID: PMC3937037.
13.    Idiopathic Pulmonary Fibrosis Clinical Research Network; Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2093-101. doi: 10.1056/NEJMoa1401739. Epub 2014 May 18. PMID: 24836309; PMCID: PMC4116664.
14.    Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest. 2007 Mar;131(3):897-899. doi: 10.1378/chest.06-2101. PMID: 17356110; PMCID: PMC2098039.
15.    Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002 Sep 21;360(9337):895-900. doi: 10.1016/S0140-6736(02)11024-5. PMID: 12354470.
16.    Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD005494. doi: 10.1002/14651858.CD005494.pub3. Update in: Cochrane Database Syst Rev. 2017 Aug 04;8:CD005494. doi: 10.1002/14651858.CD005494.pub4. PMID: 21833954.
17.    Haddad LM, Winchester JF. Clinical management of poisoning and drug overdose. Saunders. 2007;2(4):57-9.
18.    Amirshahrokhi K. The effect of Rosa canina extract against paraquat-induced lung injury. J Ard Univ Med Sci. 2020;19(4):400-9.
19.    kaffashielahi R. Protective effects of Resveratrol against chemotherapy drug Cisplatin induced hepatotoxicity in the rat. Vet Clin Pathol. 2014;7(4):286-99
20.    Jafarzadeh M, Mousavizadeh K, Joghataie MT, Asghari M. Effect of Fibroblast Growth Factor Antagonist Peptide on mouse Breast Tumor Growth and Serum Levels of Interleukin-8 and Tumor Necrosis Factor-Alpha. Yafteh. 2017;19(2):126-35.
21.    El-Aarag B, Magdy M, AlAjmi MF, Khalifa SAM, El-Seedi HR. Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries In Mice by Modifying Oxidative Stress and Apoptosis. Molecules. 2019 Apr 16;24(8):1498. doi: 10.3390/molecules24081498. PMID: 30995821; PMCID: PMC6514788.
22.    Amirshahrokhi K, Bohlooli S. Effect of methylsulfonylmethane on paraquat-induced acute lung and liver injury in mice. Inflammation. 2013 Oct;36(5):1111-21. doi: 10.1007/s10753-013-9645-8. PMID: 23595869.
23.    Amirshahrokhi K, Khalili AR. Carvedilol attenuates paraquat-induced lung injury by inhibition of proinflammatory cytokines, chemokine MCP-1, NF-κB activation and oxidative stress mediators. Cytokine. 2016 Dec;88:144-153. doi: 10.1016/j.cyto.2016.09.004. Epub 2016 Sep 10. PMID: 27619518.
24.    Suntres ZE, Shek PN. Liposomal alpha-tocopherol alleviates the progression of paraquat-induced lung damage. J Drug Target. 1995;2(6):493-500. doi: 10.3109/10611869509015919. PMID: 7773611.
25.    Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. Br J Clin Pharmacol. 2011 Nov;72(5):745-57. doi: 10.1111/j.1365-2125.2011.04026.x. PMID: 21615775; PMCID: PMC3243009.
26.    Shi X, Zhu W, Chen T, Cui W, Li X, Xu S. Paraquat induces apoptosis, programmed necrosis, and immune dysfunction in CIK cells via the PTEN/PI3K/AKT axis. Fish Shellfish Immunol. 2022 Nov;130:309-316. doi: 10.1016/j.fsi.2022.09.024. Epub 2022 Sep 17. PMID: 36126840.
27.    Xu L, Xu J, Wang Z. Molecular mechanisms of paraquat-induced acute lung injury: a current review. Drug Chem Toxicol. 2014 Apr;37(2):130-4. doi: 10.3109/01480545.2013.834361. Epub 2014 Jan 7. PMID: 24392656.
28.    Dinis-Oliveira RJ, de Pinho PG, Santos L, Teixeira H, Magalhães T, Santos A, et al. Postmortem analyses unveil the poor efficacy of decontamination, anti-inflammatory and immunosuppressive therapies in paraquat human intoxications. PLoS One. 2009 Sep 25;4(9):e7149. doi: 10.1371/journal.pone.0007149. PMID: 19779613; PMCID: PMC2745573.
29.    Chen Y, Nie YC, Luo YL, Lin F, Zheng YF, Cheng GH, Wu H, Zhang KJ, Su WW, Shen JG, Li PB. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol. 2013 Aug;58:133-40. doi: 10.1016/j.fct.2013.04.024. Epub 2013 Apr 18. PMID: 23603004.
30.    Novaes RD, Gonçalves RV, Cupertino MC, Marques DC, Rosa DD, Peluzio Mdo C, et al. Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats. Int J Exp Pathol. 2012 Jun;93(3):225-33. doi: 10.1111/j.1365-2613.2012.00808.x. Epub 2012 Mar 19. PMID: 22429505; PMCID: PMC3385921.
31.    Sharma V, Singh P, Pandey AK, Dhawan A. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res. 2012 Jun 14;745(1-2):84-91. doi: 10.1016/j.mrgentox.2011.12.009. Epub 2011 Dec 17. PMID: 22198329.
32.    Rodrigues da Silva M, Schapochnik A, Peres Leal M, Esteves J, Bichels Hebeda C, Sandri S, et al. Beneficial effects of ascorbic acid to treat lung fibrosis induced by paraquat. PLoS One. 2018 Nov 5;13(11):e0205535. doi: 10.1371/journal.pone.0205535. PMID: 30395570; PMCID: PMC6218022.
33.    Masaoka T, Akahori F, Arai S, Sakaguchi K. Effect of paraquat on plasma fibronectin, serum free hydroxyproline, serum ceruloplasmin and lung collagen content in monkeys. J Toxicol Sci. 1987 Aug;12(3):329-40. doi: 10.2131/jts.12.329. PMID: 3694721.
34.    Hosseini A, Rasaie D, Soleymani Asl S, Nili ahmadabadi A, Ranjbar A. Evaluation of the protective effects of curcumin and nanocurcumin against lung injury induced by sub-acute exposure to paraquat in rats. Toxin Rev. 2019;40:1233-41.
35.    Liu ZJ, Zhong J, Zhang M, Chen ZH, Wang JY, Chen HY, et al. The Alexipharmic Mechanisms of Five Licorice Ingredients Involved in CYP450 and Nrf2 Pathways in Paraquat-Induced Mice Acute Lung Injury. Oxid Med Cell Longev. 2019 Apr 28;2019:7283104. doi: 10.1155/2019/7283104. PMID: 31182998; PMCID: PMC6512064.
Trends in Pharmaceutical Sciences
Volume 10, Issue 4
December 2024
Pages 323-332

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