Acta Scientific Pharmaceutical Sciences (ASPS)(ISSN: 2581-5423)

Research Article Volume 5 Issue 9

Combined Inhibitory Effect of Sulindac an NSAID and Quercetin an Antioxidant on Bleomycin-induced Lung Fibrosis in Rats

Ramesh Verma1, Poonam Mehta1, Vishvesh Dalal1, Manish V Patel1 and Suresh Balakrishnan2*

1Department of Toxicology, Jai Research Foundation, Gujarat, India
2Division of Toxicology, Department of Zoology, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat, India

*Corresponding Author: Suresh Balakrishnan, Division of Toxicology, Department of Zoology, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat, India.

Received: June 23, 2021; Published: August 18, 2021


Idiopathic pulmonary fibrosis is the most prevalent chronic lung disease. Studies have suggested that ROS such as superoxide anion, hydrogen peroxide and hydroxyl radical are major mediators of lung inflammatory processes. So, the study was conducted to evaluate the ameliorative effects of quercetin alone and in combination with sulindac on lung injury induced by bleomycin. Oral administration of quercetin (100 mg/kg/day) or sulindac (20 mg/kg/day) for 20 days, attenuated the severity of bleomycin induced lung injury and fibrosis through decreasing the adverse effect of bleomycin on lung hydroxyproline contents and plasma TNF-α levels alike. However, subtle signs of toxicity still prevailed. Nevertheless, it was noticed that combined low doses of quercetin (50 mg/kg/day) and sulindac (10 mg/kg/day) provided more benefits than full separate doses of each compound on the deleterious effects accompanied bleomycin administration. Therefore, it is pertinent to presume that concurrent administration of quercetin and sulindac has synergistic effect.

Keywords: Idiopathic Pulmonary Fibrosis; Bleomycin; Quercetin; Sulindac; Hydroxyproline


  1. Atzori L., et al. “Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol”. Thorax 59 (2004): 217-223.
  2. Beigh S., et al. “Bleomycin-induced pulmonary toxicopathological changes in rats and its prevention by walnut extract”. Biomedicine and Pharmacotherapy 94 (2017): 418-429.
  3. Berman K., et al. “Sulindac Enhances Tumor Necrosis Factor-α-mediated Apoptosis of Lung Cancer Cell Lines by Inhibition of Nuclear Factor-κB”. Clinical Cancer Research 8 (2002): 354-360.
  4. Boots AW., et al. “Health effects of quercetin: from antioxidant to nutraceutical”. European Journal of Pharmacology 585 (2008): 325-337.
  5. Cooper Jr JAD. “Pulmonary fibrosis”. American Journal of Respiratory Cell and Molecular Biology 22 (2000): 520-523.
  6. Dharani M and Kalava S. “Ameliorative effect of Punica granatum L. Against bleomycin induced pulmonary fibrosis in rats”. International Journal of Pharmaceutical Sciences and Research4 (2015): 1465-1472.
  7. Edwards CA., et al. “Modified Assay for Determination of Hydroxyproline in a Tissue Hydrolyzate”. Clinica Chimica Acta 104 (1980): 161-167.
  8. El-Khoulya D., et al. “Thymoquinone blocks lung injury and fibrosis by attenuating bleomycin-induced oxidative stress and activation of nuclear factor Kappa-B in rats”. Toxicology 302 (2012): 106-113.
  9. Eynott PR., et al. “Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness”. European Journal of Pharmacology 452 (2002): 123-133.
  10. Filderman AE., et al. “Alteration in pulmonary protective enzymes following systemic bleomycin treatment in mice”. Biochemistry and Pharmacology 37 (1988): 1111-1116.
  11. Gad SC., et al. “Statistics for Toxicology, third ed”. In Hayes, A.W. (Eds), Principles and Methods of Toxicology, Raven Press Ltd., New York (1994): 221-274.
  12. Galvan L., et al. “Inhibition of bleomycin-induced DNA breakage by superoxide dismutase”. Cancer Research 41 (1981): 5103-5106.
  13. Gao J., et al. “Antifibrosis effects of total glucosides of Danggui-Buxue-Tang in a rat model of bleomycin-induced pulmonary fibrosis”. Journal of Ethnopharmacology 136 (2011): 21-26.
  14. Grande NR., et al. “Lung fibrosis induced by bleomycin: structural changes and overview of recent advances”. Scanning Microscope 12 (1998): 487-494.
  15. Gross TJ and Hunninghake GW. “Idiopathic pulmonary fibrosis”. The New England Journal of Medicine 16 (2001): 517-525.
  16. Hagiwara SI., et al. “Aerosolized administration of N-acetyl cysteine attenuates lung fibrosis induced by bleomycin in mice”. American Journal of Respiratory and Critical Care Medicine 162 (2000): 225-231.
  17. Ho BY., et al. “Dimerumic Acid Inhibits SW620 Cell Invasion by Attenuating H2O2-Mediated MMP-7 Expression via JNK/C-Jun and ERK/C-Fos Activation in an AP-1-Dependent Manner”. International Journal of Biological Sciences6 (2011): 869-880.
  18. Kakkar P., et al. “A Modified spectrophotometric assay of superoxide dismutase”. Indian Journal of Biochemistry and Biophysics 21 (1984): 130-132.
  19. Kalayarasan S., et al. “Diallyl sulfide attenuates bleomycin- induced pulmonary fibrosis: Critical role of iNOS, NF-κB, TNF- α and IL-1β”. Life Sciences 82 (2008): 1142-1153.
  20. Keane MP., et al. “IL-12 attenuates bleomycin induced pulmonary fibrosis”. American Journal of Physiology - Lung Cellular and Molecular Physiology 281 (2001): 92-97.
  21. Liang S., et al. “The role of NADPH oxidases (NOXs) in liver fibrosis and the activation of myofibroblasts”. Frontiers in Physiology 7 (2016): 17.
  22. Liang X., et al. “Effect of Feining on bleomycin-induced pulmonary injuries in rats”. Journal of Ethnopharmacology 134 (2011): 971-976.
  23. Luck H. “A spectrophotometric method for the estimation of catalase”. in: Bergmeyer, H.U., (Eds.), Methods of enzymatic analysis. Academic Press, New York (1963): 886-887.
  24. Madala SK., et al. “MEK-ERK Pathway Modulation Ameliorates Pulmonary Fibrosis Associated with Epidermal Growth Factor Receptor Activation”. American Journal of Respiratory Cell and Molecular Biology 46 (2012): 380-388.
  25. Materska M and Perucka I. “Antioxidant Activity of the Main Phenolic Compounds Isolated from Hot Pepper Fruit (Capsicum annuum L.)”. Journal of Agricultural and Food Chemistry 53 (2005): 1750-1756.
  26. Moeller A., et al. “The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?” The International Journal of Biochemistry and Cell Biology 40 (2008): 362-382.
  27. Myers JM., et al. “Redox activation of Fe (III)-thiosemicarbazones and Fe (III)-bleomycin by thioredoxin reductase: specificity of enzymatic redox centers and analysis of reactive species formation by ESR spin trapping”. Free Radical Biology and Medicine 60 (2013): 183-194.
  28. Ohkawa H., et al. “Assay of lipoperoxides in animal tissues by thiobarbituric acid reaction”. Analytical Biochemistry 95 (1979): 351-358.
  29. Oku H., et al. “Antifibrotic action of pirfenidone and prednisolone: Different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis”. European Journal of Pharmacology 590 (2008): 400-408.
  30. Ortiz LA., et al. “Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kB and AP-1”. American Journal of Physiology - Lung Cellular and Molecular Physiology 282 (2002): 1209-1221.
  31. Oury TD., et al. “Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin”. American Journal of Respiratory Cell and Molecular Biology 25 (2001): 164-169.
  32. Pallai A., et al. “Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications”. The Journal of Immunology3 (2016): 1146-1157.
  33. Park MH and Hong JT. “Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches”. Cells 5 (2016): 15.
  34. Razzaque MS and Taguchi T. “Pulmonary fibrosis: cellular and molecular events”. Pathology International 53 (2003): 133-145.
  35. Reyfman PA., et al. “Transcriptional profiling of sorted alveolar macrophages reveals homology between human fibrotic interstitial lung disease and an animal model of pulmonary fibrosis. In B97. Flipping the Switch: Determinants of Fibrosis”. American Thoracic Society (2017): A4667-A4667.
  36. Rocca J., et al. “New use for an old drug: COX‐independent anti‐inflammatory effects of sulindac in models of cystic fibrosis”. British Journal of Pharmacology11 (2016): 1728-1741.
  37. Sogut S., et al. “Erdosteine prevents belomycin-induced pulmonary fibrosis in rats”. European Journal of Pharmacology 494 (2004): 213-220.
  38. Soumyakrishnan S and Sudhandiran G. “Daidzein attenuates inflammation and exhibits antifibrotic effect against bleomycin-induced pulmonary fibrosis in Wistar rats”. Biomedicine and Preventive Nutrition 1 (2011): 236-244.
  39. Spagnolo P., et al. “Idiopathic pulmonary fibrosis: recent advances on pharmacological therapy”. Pharmacology and Therapeutics 152 (2015): 18-27.
  40. Sriram N., et al. “Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling”. Pulmonary Pharmacology and Therapeutics 22 (2009): 221-236.
  41. Szapiel SV., et al. “Bleomycin -induced interstitial pulmonary disease in the nude, athymic mouse”. American Review of Respiratory Diseases 120 (1979): 893-899.
  42. Tajima S., et al. “Effects of edaravone, a free-radical scavenger, on bleomycin-induced lung injury in mice”. European Respiratory Journal5 (2008): 1337-1343.
  43. Tang Y., et al. “Quercetin prevents ethanol-induced dyslipidemia and mitochondrial oxidative damage”. Food and Chemical Toxicology 50 (2012): 1194-1200.
  44. Teixeira KC., et al. “Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine”. Pulmonary Pharmacology and Therapeutics 21 (2008): 309-316.
  45. Vaish V., et al. “Role of Sulindac and Celecoxib in the regulation of angiogenesis during the early neoplasm of colon: Exploring PI3-K/PTEN/Akt pathway to the canonical Wnt/b-catenin signaling”. Biomedicine and Pharmacotherapy 66 (2012): 354-367.
  46. Vane JR., et al. “Cyclooxygenases 1 and 2”. Annual Review of Pharmacology and Toxicology 38 (1998): 97-120.
  47. Varol C., et al. “Macrophages: development and tissue specialization”. Annual Review of Immunology 33 (2015): 643-675.
  48. Verma R., et al. “Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats”. Environmental Toxicology and Pharmacology 36 (2013): 769-778.
  49. Wang HD., et al. “Bilirubin ameliorates bleomycin-induced pulmonary fibrosis in rats”. American Journal of Respiratory and Critical Care Medicine 165 (2002): 406-411.
  50. Wang QJ., et al. “Amelioration of bleomycin-induced pulmonary fibrosis in hamsters by combined treatment with taurine and niacin”. Biochemistry and Pharmacology 42 (1991): 1115-1122.
  51. Weissler JC. “Idiopathic pulmonary fibrosis: cellular and molecular pathogenesis”. American Journal of the Medical Sciences 297 (1989): 92-104.
  52. Xin Wei X., et al. “A phosphoinositide 3-kinase-γ inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats”. Biochemical and Biophysical Research Communications 397 (2010): 311-317.
  53. Zhao L., et al. “Neferine, a bisbenzylisoquinline alkaloid attenuates bleomycin induced pulmonary fibrosis”. European Journal of Pharmacology 627 (2010): 304-312.
  54. Zhou X., et al. “Inhibitory effects of Hu-qi-yin on the bleomycin-induced pulmonary fibrosis in rats”. Journal of Ethnopharmacology 111 (2007): 255-264.


Citation: Suresh Balakrishnan., et al. “Combined Inhibitory Effect of Sulindac an NSAID and Quercetin an Antioxidant on Bleomycin-induced Lung Fibrosis in Rats". Acta Scientific Pharmaceutical Sciences 5.9 (2020): 55-65.


Copyright: © 2021 Suresh Balakrishnan., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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