Protective Effect of Co Q10 and Candesartan on Bleomyycin Induced Lung Fibrosis in Rats
DOI:
https://doi.org/10.32947/ajps.v21i1.787Keywords:
pulmonary fibrosis, bleomycin, CoQ10, candesartan, glutathione, arachidonate 5 lipoxygenase.Abstract
Fibrosis of the lungs is the final phase of many lung illnesses. Its characterized by excessive matrix production leading to the normal lung architecture destruction and eventually death. CoQ10 is an essential constituent of membrane oxidoreductase System. It is an intracellularly localized antioxidant
enzyme that is endogenously synthesized in humans. CoQ10 protects cellular components from destruction by free radical-induced oxidative damage. candesartan is a selective antagonist of angiotensin II type 1 receptor (AT1) and is widely employed for treatment of hypertension. Most up to date research shows angiotensin II close involvement with damage and fibrosis process in tissues of organs of circulation.
Objective: This animal study was designed to investigate the effect of Co Q10 and candesartan as antifibrotic agents against pulmonary fibrosis focusing on selected markers involved in pulmonary fibrosis.
Materials and Method: 48 rats divided randomly into four groups, each consisting of 12 male rats. Group I: (Control group), the rats in this group received single injection of 0.2 ml normal saline via intratracheal route. Group II: (The BLM group), received BLM (8.3 U/kg) as a single dose via the intratracheal rout. Group III: (BLM+CoQ10 group) rats receive BLM (8.3 U/kg) as sulfate salt dissolved in 0.1 ml of normal saline via the intratracheal instillation concomitant with 100 mg/kg co Q 10 per day orally for 5 days before and 10 days after BLM injection. Group IV: (BLM+ candesartan group) rats receive BLM (8.3 U/kg) as sulfate salt dissolved in 0.1 ml of normal saline via the intratracheal instillation concomitant with (10 mg/kg) candesartan per day orally for 5 days before and 10 days after BLM injection. The studied serum biomarkers were glutathione, arachidonate 5 lipoxygenase in addition to histopathological examination using trichrome stain.
Results: serum GSH concentration was lower in BLM group in comparison with the control group and the (BLM+ CoQ10) but this difference is not statistically significant. The serum GSH levels showed a significant(P<0.05) elevation in (BLM+ Candesartan) group when compared with the levels in the BLM group. The serum ALOX5 concentration was significantly elevated in BLM group in comparison with the control group (P < 0.05). The serum ALOX5 levels were highly significantly lower in (BLM +CoQ10) (P < 0.01) and very highly significantly lower in the (BLM+ Candesartan) group (P < 0.001) when comparing it with the levels in the BLM group. furthermore, histologically CoQ10 and candesartan showed reduction in the numbers of inflammation cells and a decrease in the damage to the lung architecture and fibrosis induced by bleomycin.
Conclusion: CoQ10 and candesartan decrease pulmonary fibrosis induced by bleomycin in male rats.
References
- Wuyts WA, Agostini C, Antoniou KM, Bouros D, Chambers RC, Cottin V, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013;41(5):1207-18. DOI: https://doi.org/10.1183/09031936.00073012
- Uhal BD, Kyong Kim J, Li X, Molina-Molina MJCpd. Angiotensin-TGF-β1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages. Curr Pharm Des. 2007;13(12):1247-56. DOI: https://doi.org/10.2174/138161207780618885
- Wilson M, Wynn TJMi. Pulmonary fibrosis: pathogenesis, etiology and regulation. 2009;2(2):103. DOI: https://doi.org/10.1038/mi.2008.85
- Selman M, King TE, Pardo AJAoim. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136-51. DOI: https://doi.org/10.7326/0003-4819-134-2-200101160-00015
- Strieter RM, Mehrad B. New mechanisms of pulmonary fibrosis. Chest. 2009;136(5):1364-70. DOI: https://doi.org/10.1378/chest.09-0510
- Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3(4):350-6. DOI: https://doi.org/10.1513/pats.200601-001TK
- Khalil N, Xu YD, O'Connor R, Duronio VJJoBC. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-β1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. 2005;280(52):43000-9. DOI: https://doi.org/10.1074/jbc.M510441200
- Reinert T, Baldotto CSdR, Nunes FAP, Scheliga AAdSJJoCR. Bleomycin-induced lung injury. 2013;2013. DOI: https://doi.org/10.1155/2013/480608
- Allawzi A, Elajaili H, Redente EF, Nozik-Grayck E. Oxidative Toxicology of Bleomycin: Role of the Extracellular Redox Environment. Curr Opin Toxicol. 2019;13:68-73. DOI: https://doi.org/10.1016/j.cotox.2018.08.001
- Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol. 1991;65(2):81-94. DOI: https://doi.org/10.1007/BF02034932
- Tsai K-L, Huang Y-H, Kao C-L, Yang D-M, Lee H-C, Chou H-Y, et al. A novel mechanism of coenzyme Q10 protects against human endothelial cells from oxidative stress-induced injury by modulating NO-related pathways. 2012;23(5):458-68. DOI: https://doi.org/10.1016/j.jnutbio.2011.01.011
- Linnane AW, Kios M, Vitetta LJM. Coenzyme Q10–Its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolome. Mitochondrion. 2007;7:S51-S61. DOI: https://doi.org/10.1016/j.mito.2007.03.005
- Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutr Rev. 2007;65(6 Pt 1):286-93. DOI: https://doi.org/10.1111/j.1753-4887.2007.tb00306.x
- Ardiana F, Lestari ML, Indrayanto G. Candesartan cilexetil. Profiles of Drug Substances, Excipients and Related Methodology. 37: Elsevier; 2012. p. 79-112. DOI: https://doi.org/10.1016/B978-0-12-397220-0.00003-9
- Hara H, Takeda N, Komuro I. Pathophysiology and therapeutic potential of cardiac fibrosis. Inflamm Regen. 2017;37(1):13. DOI: https://doi.org/10.1186/s41232-017-0046-5
- Otsuka M, Takahashi H, Shiratori M, Chiba H, Abe S. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax. 2004;59(1):31-8. DOI: https://doi.org/10.1136/thx.2003.000893
- Rivera-Ortega P, Molina-Molina M. Interstitial Lung Diseases in Developing Countries. Ann Glob Health. 2019;85(1). DOI: https://doi.org/10.5334/aogh.2414
- Marshall RP, McANULTY RJ, Laurent GJJAjor, medicine cc. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med. 2000;161(6):1999-2004. DOI: https://doi.org/10.1164/ajrccm.161.6.9907004
- Molteni A, Moulder JE, Cohen EF, Ward WF, Fish BL, Taylor JM, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int J Radiat Biol. 2000;76(4):523-32. DOI: https://doi.org/10.1080/095530000138538
- Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis. Fibrogenesis Tissue Repair. 2015;8(1):7. DOI: https://doi.org/10.1186/s13069-015-0023-z
- Zaghloul MS, Abdel-Salam RA, Said E, Suddek GM, Salem HA-RJEjob, sciences a. Attenuation of Bleomycin-induced pulmonary fibrosis in rats by flavocoxid treatment. Egyptian Journal of Basic and Applied Sciences. 2017;4(4):256-63. DOI: https://doi.org/10.1016/j.ejbas.2017.10.005
- Walters DM, Kleeberger SRJCpip. Mouse models of bleomycin‐induced pulmonary fibrosis. 2008;40(1):5.46. 1-5.. 17. DOI: https://doi.org/10.1002/0471141755.ph0546s40
- Ferguson GD, Bridge WJ. The glutathione system and the related thiol network in Caenorhabditis elegans. Redox Biol. 2019;24:101171. DOI: https://doi.org/10.1016/j.redox.2019.101171
- Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. The International Journal of Biochemistry & Cell Biology. 2011;43(1):154-62. DOI: https://doi.org/10.1016/j.biocel.2010.10.013
- Gaucher C, Boudier A, Bonetti J, Clarot I, Leroy P, Parent M. Glutathione: Antioxidant Properties Dedicated to Nanotechnologies. Antioxidants (Basel). 2018;7(5):62. DOI: https://doi.org/10.3390/antiox7050062
- Chen J, Shi Y, He L, Hao H, Wang B, Zheng Y, et al. Protective roles of polysaccharides from Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats. Int J Biol Macromol. 2016;92:278-81. DOI: https://doi.org/10.1016/j.ijbiomac.2016.07.005
- McMillan DH, van der Velden JL, Lahue KG, Qian X, Schneider RW, Iberg MS, et al. Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase pi. JCI Insight. 2016;1(8). DOI: https://doi.org/10.1172/jci.insight.85717
- Lone Y, Bhide M, Koiri RK. Amelioratory effect of coenzyme Q10 on potential human carcinogen Microcystin-LR induced toxicity in mice. Food Chem Toxicol. 2017;102:176-85. DOI: https://doi.org/10.1016/j.fct.2017.02.018
- Tamuli S, Kakati S, Das SJIJoPS, Research. Comparative studies of efficacy and effect on oxidative stress of atenolol and candesartan in the hypertensive patients of North East India. 2015;6(4).
- Muda P, Kampus P, Zilmer M, Ristimae T, Fischer K, Zilmer K, et al. Effect of antihypertensive treatment with candesartan or amlodipine on glutathione and its redox status, homocysteine and vitamin concentrations in patients with essential hypertension. J Hypertens. 2005;23(1):105-12. DOI: https://doi.org/10.1097/00004872-200501000-00019
- Uduman S, Thattakudian MS, Reddy RB, Punuru P, Chakka G, Karunakaran GJAips. Protective role of ramipril and candesartan against myocardial ischemic reperfusion injury: a biochemical and transmission electron microscopical study. Advances in Pharmacological and Pharmaceutical Sciences 2016;2016. DOI: https://doi.org/10.1155/2016/4608979
- Fouad AA, Al-Sultan AI, Refaie SM, Yacoubi MT. Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice. Toxicology. 2010;274(1-3):49-56. DOI: https://doi.org/10.1016/j.tox.2010.05.007
- Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015;6:297-310. DOI: https://doi.org/10.1016/j.redox.2015.08.006
- Alabbassi MG. The Possible Protective Effects of Zileuton against Pulmonary Fibrosis Induced by Amiodarone in Male Rats. Journal of Natural Sciences Research
- Wiley CD, Brumwell AN, Davis SS, Jackson JR, Valdovinos A, Calhoun C, et al. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI Insight. 2019;4(24). DOI: https://doi.org/10.1172/jci.insight.130056
- Tsai KL, Chen LH, Chiou SH, Chiou GY, Chen YC, Chou HY, et al. Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. Mol Nutr Food Res. 2011;55 Suppl 2(S2):S227-40. DOI: https://doi.org/10.1002/mnfr.201100147
- Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol. 2000;157(1):177-87. DOI: https://doi.org/10.1016/S0002-9440(10)64529-4
- Mohamed DI, Khairy E, Tawfek SS, Habib EK, Fetouh MA. Coenzyme Q10 attenuates lung and liver fibrosis via modulation of autophagy in methotrexate treated rat. Biomed Pharmacother. 2019;109:892-901. DOI: https://doi.org/10.1016/j.biopha.2018.10.133
- Oto G, Ekin S, Çelikezen FÇ, Yener Z, Tanrıtanır P, Özdemir H, et al. cytoprotective effects of boric acid and coenzyme q 10 therapy on induced pulmonary fibrosis in response to intratracheal administration of bleomycin in rats. 2013.
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