Does gallic acid improve cardiac function by attenuation of oxidative stress and inflammation in an elastase-induced lung injury?

Document Type : Original Article


Department of Physiology, Physiology Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective(s): Cardiovascular disease has an important role in mortality caused by lung injury. Emphysema is associated with impaired pulmonary gas exchange efficiency and airflow limitation associated with small airway inflammation. The aim was to evaluate the interactions between lung injury, inflammation, and cardiovascular disease. Since gallic acid has antioxidant and anti-inflammatory effects, we hypothesized that gallic acid protects the lung and the related heart dysfunction in elastase-induced lung injury.
Materials and Methods: Forty-eight Sprague-Dawley male rats were randomly divided into six groups: Control, Porcine pancreatic elastase (PPE) , PPE+GA, and 3 groups for different doses of gallic acid (GA 7.5, GA 15, GA 30 mg/kg). PPE was injected intra-tracheally on days 1 and 10 of the test. In each group, electrocardiography, hemodynamic parameters, oxidative stress, and bronchoalveolar lavage fluid were examined.
Results: PPE administration showed a decrease in HR and QRS voltage of electrocardiogram parameters, as well as in hemodynamic parameters (P<0.05, P<0.01, and P<0.001) and superoxide dismutase (SOD)  (P<0.05). Tumor Necrosis Factor α (TNF-α) (P<0.001), interleukin 6 (IL-6) (P<0.001), interleukin 6 (MDA) (P<0.001), and the total number of white blood cells (P<0.001) showed an increase in PPE groups. Gallic acid preserved the values of hemodynamic properties, oxidative stress, inflammation, and electrocardiogram parameters in comparison to the PPE group.
Conclusion: Briefly, this study showed the valuable effect of gallic acid in cardiac dysfunction related to elastase-induced lung injury. These findings suggested that gallic acid, as a natural antioxidant, has a potential therapeutic effect on preventing oxidative stress, inflammation, and subsequent cardiovascular disease.


1. Tsukamoto M, Mori T, Wang KY, Okada Y, Fukuda H, Naito K, et al. Systemic bone loss, impaired osteogenic activity and type I muscle fiber atrophy in mice with elastase-induced pulmonary emphysema: Establishment of a COPD-related osteoporosis mouse model. Bone 2019;120:114-124.
2. MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:258-266.
3. Urban MH, Eickhoff P, Funk GC, Burghuber OC, Wolzt M, Valipour A. Increased brachial intima-media thickness is associated with circulating levels of asymmetric dimethylarginine in patients with COPD. Int J Chron Obstruct Pulmon Dis 2017;12: 169-176.
4. Parr DG, White AJ, Bayley DL, Guest PJ, Stockley RA. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study. Respir Res 2006 ;7:136.
5. Lombard C, Arzel L, Bouchu D, Wallach J, Saulnier J. Human leukocyte elastase hydrolysis of peptides derived from human elastin exon 24. Biochimie 2006;88:1915-1921.
6. Owen CA. Proteinases and oxidants as targets in the treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:373-385.
7. Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003;21:347-360.
8. Sin DD, Man SP. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514-1519.
9. Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med 2003;114:758-762.
10. Van Eeden S, Leipsic J, Paul Man SF, Sin DD. The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med 2012;186:11-16.
11. Gupta NK, Agrawal RK, Srivastav AB, Ved ML. Echocardiographic evaluation of heart in chronic obstructive pulmonary disease patient and its co-relation with the severity of disease. Lung India 2011;28:105-109.
12. Leuchte HH, Baumgartner RA, Nounou ME, Vogeser M, Neurohr C, Trautnitz M, et al. Brain natriuretic peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit Care Med 2006;173:744-750.
13. Maclay JD, McALLISTER DA, MacNEE W. Cardiovascular risk in chronic obstructive pulmonary disease. Respirology 2007;12:634-641.
14. Đorović J, Marković JM, Stepanić V, Begović N, Amić D, Marković Z. Influence of different free radicals on scavenging potency of gallic acid. J Mol Model 2014 ;20:2345.
15. Ahmadi-Naji R, Heidarian E, Ghatreh-Samani K. Evaluation of the effects of the hydroalcoholic extract of Terminalia chebula fruits on diazinon-induced liver toxicity and oxidative stress in rats. Avicenna J Phytomed 2017;7:454-466.
16. Badhani B, Sharma N, Kakkar R. Gallic acid: a versatile anti-oxidant with promising therapeutic and industrial applications. RSC Adv 2015;5:27540-27557.
17. Faried A, Kurnia D, Faried LS, Usman N, Miyazaki T, Kato H, et al. Anticancer effects of gallic acid isolated from Indonesian herbal medicine, Phaleria macrocarpa (Scheff.) Boerl, on human cancer cell lines. Int J Oncol 2007;30:605-613.
18. Uniyal S, Dhasmana A, Tyagi A, Muyal JP. ATRA reduces inflammation and improves alveolar epithelium regeneration in emphysematous rat lung. Biomed Pharmacother 2018;108:1435-1450.
19. Badavi M, Sadeghi N, Dianat M, Samarbafzadeh A. Effects of gallic acid and cyclosporine a on anti-oxidant capacity and cardiac markers of rat isolated heart after ischemia/reperfusion. Iran Red Crescent Med J 2014;16: 16424.
20. Dianat M, Radan M, Badavi M, Mard SA, Bayati V, Ahmadizadeh M. Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 anti-oxidant system in preventing oxidative stress. Respir Res 2018;19:58.
21. Zaghloul MS, Said E, Suddek GM, Salem HA. Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis. Life Sci 2019 ;235:116794.
22. Vosooghi S, Mahmoudabady M, Neamati A, Aghababa H. Preventive effects of hydroalcoholic extract of saffron on hematological parameters of experimental asthmatic rats. Avicenna J Phytomed 2013;3:279-287.
23. Gao ML, Chen L, Li YF, Xue XC, Chen L, Wang LN, et al. Synergistic increase of oxidative stress and tumor markers in PAH-exposed workers. Asian Pac J Cancer Prev 2014 ;15:7105-7112.
24. Radan M, Dianat M, Badavi M, Mard SA, Bayati V, Goudarzi G. Gallic acid protects particulate matter (PM 10) triggers cardiac oxidative stress and inflammation causing heart adverse events in rats. Environ Sci Pollut Res Int 2019 ;26:18200-18207.
25. Kheiry M, Dianat M, Badavi M, Mard SA, Bayati V. p-Coumaric acid protects cardiac function against lipopolysaccharide-induced acute lung injury by attenuation of oxidative stress. Iran J Basic Med Sci 2019 ;22:949-955.
26. Dianat M , Radmanesh E , Badavi M , Mard SA , Goudarzi G. Disturbance effects of PM 10 on iNOS and eNOS mRNA expression levels and anti-oxidant activity induced by ischemia–reperfusion injury in isolated rat heart: protective role of vanillic acid. Environ Sci Pollut Res Int 2016;23:5154-5165.
27. Wright JL, Cosio M, Churg A. Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 2008;295:L1-L15.
28. Antunes MA, Rocco PR. Elastase-induced pulmonary emphysema: insights from experimental models. An Acad Bras Cienc 2011;83:1385-1396.
29. Lüthje L, Raupach T, Michels H, Unsöld B, Hasenfuss G, Kögler H, et al. Exercise intolerance and systemic manifestations of pulmonary emphysema in a mouse model. Respir Res 2009 ;10:7.
30. Smith MC, Wrobel JP. Epidemiology and clinical impact of major comorbidities in patients with COPD. Int J Chron Obstruct Pulmon Dis 2014;9:871-888.
31. Agusti À, Soriano JB. COPD as a systemic disease. COPD 2008 ;5:133-138.
32. Visca D, Aiello M, Chetta A. Cardiovascular function in pulmonary emphysema. Biomed Res Int 2013;2013:184678.
33. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA 1994;272:1497-1505.
34. Chung K, Adcock I. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J 2008 ;31:1334-1356.
35. Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469-473.
36. Donovan C, Starkey MR, Kim RY, Rana BM, Barlow JL, Jones B, et al. Roles for T/B lymphocytes and ILC2s in experimental chronic obstructive pulmonary disease. J Leukoc Biol 2019 ;105:143-150.
37. Arellano-Orden E, Calero C, López-Ramírez C, Sánchez-López V, López-Villalobos JL, Arranz MA, et al. Evaluation of lung parenchyma, blood vessels, and peripheral blood lymphocytes as a potential source of acute phase reactants in patients with COPD. Int J Chron Obstruct Pulmon Dis 2019;14:1323-1332.
38. Lin J, Xu F, Wang G, Kong L, Luo Q, Lv Y, et al. Paeoniflorin attenuated oxidative stress in rat COPD model induced by cigarette smoke. Evid Based Complement Alternat Med 2016;2016:1698379.
39. Sauleda J, Garci ́a-palmer FJ, Gonza ́ lez GE, Palou A, A gusti ́ AG. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000;161:32-35.
40. Shapiro SD. Animal models for COPD. Chest 2000;117:223-227.
41. Taguchi L, Pinheiro NM, Olivo CR, Choqueta-Toledo A, Grecco SS, Lopes FD, et al. A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-κB, oxidative stress and metalloproteinases. Respir Res 2015;16:79-93.
42. Kawakami M, Matsuo Y, Yoshiura K, Nagase T, Yamashita N. Sequential and quantitative analysis of a murine model of elastase-induced emphysema. Biol Pharm Bull 2008 ;31:1434-1438.
43. Anciaes AM, Olivo CR, Prado CM, Kagohara KH, Pinto TD, Moriya HT, et al. Respiratory mechanics do not always mirror pulmonary histological changes in emphysema. Clinics 2011;66:1797-1803.
44. Ofulue AF, Ko M. Effects of depletion of neutrophils or macrophages on development of cigarette smoke-induced emphysema. Am J Physiol Lung Cell Mol Physiol 1999;277:L97-L105.
45. De Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM. Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 1996;153:633-637.
46. Tamagawa E, Suda K, Wei Y, Xing L, Mui T, Li Y, et al. Endotoxin-induced translocation of interleukin-6 from lungs to the systemic circulation. Innate Immun 2009 ;15:251-258.
47. Wedzicha JA, Seemungal TA, MacCallum PK, Paul EA, Donaldson GC, Bhowmik A, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 2000;84:210-215.
48. Pinto-Plata VM, Müllerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, et al. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax 2006 ;61:23-28.
49. Yao Y, Zhou J, Diao X, Wang S. Association between tumor necrosis factor-α and chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis 2019 ;13:1753466619866096.
50. Fujita M, Ouchi H, Ikegame S, Harada E, Matsumoto T, Uchino J, et al. Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice. Int J Chron Obstruct Pulmon Dis 2016;11:1705-1712.
51. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, et al. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414-1418.
52. Kersul AL, Iglesias A, Ríos Á, Noguera A, Forteza A, Serra E, et al. Molecular mechanisms of inflammation during exacerbations of chronic obstructive pulmonary disease. Arch Bronconeumol 2011;47:176-183.
53. Pashkow FJ. Oxidative stress and inflammation in heart disease: do anti-oxidants have a role in treatment and/or prevention? Int J Inflam 2011;2011:514623.
54. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-2618.
55. Montaño M , Cisneros J, Ramírez-Venegas A, Pedraza-Chaverri J, Mercado D, Ramos C, et al. Malondialdehyde and superoxide dismutase correlate with FEV(1) in patients with COPD associated with wood smoke exposure and tobacco smoking. Inhal Toxicol 2010;22:868-674.
56. Corrales-Medina VF, Musher DM, Wells GA, Chirinos JA, Chen L, Fine MJ. Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality. Circulation 2012 ;125:773-781.
57. Anciães AM, Olivo CR, Prado CM, Kagohara KH, Pinto Tda S, Moriya HT, et al. Respiratory mechanics do not always mirror pulmonary histological changes in emphysema. Clinics (Sao Paulo) 2011;66:1797-1803.
58. Bras NF, Goncalves R, Mateus N, Fernandes PA, Ramos MJ, de Freitas V. Inhibition of pancreatic elastase by polyphenolic compounds. J Agric Food Chem 2010;58:10668-10676.
59. Culpitt SV, Rogers DF, Fenwick PS, Shah P, De Matos C, Russell RE, et al. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003;58:942-946.
60. Akbari G. Molecular mechanisms underlying gallic acid effects against cardiovascular diseases: An update review. Avicenna J Phytomed 2020;10:11-23.
61. Appeldoorn CC, Bonnefoy A, Lutters BC, Daenens K, van Berkel TJ, Hoylaerts MF, et al. Gallic acid antagonizes P-selectin–mediated platelet–leukocyte interactions: implications for the French paradox. Circulation 2005;111:106-112.
62. El-Hussainy EH, Hussein AM, Abdel-Aziz A, El-Mehasseb I. Effects of aluminum oxide (Al2O3) nanoparticles on ECG, myocardial inflammatory cytokines, redox state, and connexin 43 and lipid profile in rats: possible cardioprotective effect of gallic acid. Can J Physiol Pharmacol 2016 ;94:868-678.
63. Prince PSM, Priscilla H, Devika PT. Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats. Eur J Pharmacol 2009;615:139-143.
64. Ramezani-Aliakbari F, Badavi M, Dianat M, Mard SA, Ahangarpour A. Effects of gallic acid on hemodynamic parameters and infarct size after ischemia-reperfusion in isolated rat hearts with alloxan-induced diabetes. Biomed Pharmacother 2017;96:612-618.
65. Omóbòwálé TO, Oyagbemi AA, Folasire AM, Ajibade TO, Asenuga ER, Adejumobi OA, et al. Ameliorative effect of gallic acid on doxorubicin-induced cardiac dysfunction in rats. J Basic Clin Physiol Pharmacol 2018;29:19-27.
66. Badavi M, Barzegar F, Dianat M, Mard SA. Evaluation of the effect of gallic acid on QT interval prolongation and serum billirubin in rat model of liver cirrhosis. Res J Pharm Biol Chem Sci 2016;7:586-592.
67. Dianat M, Akbari G, Badavi M. Antidysrhythmic effects of aallic acid on CaCl2-induced arrhythmia in rat. Int J Res Dev Pharm L Sc 2013;2:686-689.
68. Zhou R, Xu Q, Zheng P, Yan L, Zheng J, Dai G. Cardioprotective effect of fluvastatin on isoproterenol-induced myocardial infarction in rat. Eur J Pharmacol 2008;586:244-250.
69. Osada M, Netticadan T, Tamura K, Dhalla NS. Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning. Am J Physiol 1998;274:H2025-2034.
70. Goyal S, Siddiqui MK, Siddiqui KM, Arora S, Mittal R, Joshi S, et al. Cardioprotective effect of ‘Khamira Abresham Hakim Arshad Wala’a unani formulation in isoproterenol-induced myocardial necrosis in rats. Exp Toxicol Pathol 2010 ;62:61-74.
71. Giussani DA, Camm EJ, Niu Y, Richter HG, Blanco CE, Gottschalk R, et al. Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress. PLoS One 2012;7: 31017-31026.