Rosuvastatin Affects Tracheal Responsiveness, Bronchoalveolar Lavage Inflammatory Cells, and Oxidative Stress Markers in Hyperlipidemic and Asthmatic Rats

  • Saeideh Saadat Department of Physiology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran AND  Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  • Amin Mokhtari-Zaer Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran AND Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Mousa-Al-Reza Hadjzadeh Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran AND Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Mohammad Hossein Boskabady Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran AND Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Keywords: Asthma, Hyperlipidemia, Oxidative stress, Rosuvastatin


Statins provide greater protection than predicted from just cholesterol-lowering effects, which is possibly mediated by other pleiotropic actions. This study aimed to examine the possible interaction effect of asthma on lipid profiles and evaluate the effect of rosuvastatin treatment on asthma. The animals were assigned into (1) control, (2) asthmatic, (3) hyperlipidemic, (4) asthmatic-hyperlipidemic, (5) rosuvastatin (40 mg/kg/day intraperitoneally, for 3 weeks)-treated asthmatic, (6) rosuvastatin-treated hyperlipidemic and (7) rosuvastatin-treated asthmatic-hyperlipidemic groups. Tracheal responsiveness to methacholine and ovalbumin, total and differential WBC (white blood cell) counts, and oxidative stress markers in bronchoalveolar lavage fluid (BALF) were evaluated. In the asthmatic and asthmatic-hyperlipidemic groups, tracheal responsiveness to ovalbumin, total WBC count, numbers of eosinophils, neutrophils, and monocytes were higher than the control group (p<0.001). A left-ward shift in the concentration-response curves to methacholine, an increase in nitrite and malondialdehyde concentrations, and a decrease in total thiol content, superoxide dismutase and catalase activities were also observed in the asthmatic and asthmatic-hyperlipidemic groups compared to control group (p<0.01 to p<0.001). Beyond lipid-lowering effect in the treated hyperlipidemic and asthmatic-hyperlipidemic groups, rosuvastatin treatment decreased tracheal responsiveness to methacholine, reduced total WBC count, the numbers of eosinophils, neutrophils, and monocytes, as well as decreased malondialdehyde concentration, and increased total thiol content, superoxide dismutase and catalase activities in treated asthmatic and asthmatic-hyperlipidemic groups (p<0.05 to p<0.001). The improving effect of rosuvastatin on asthmatic and asthmatic-hyperlipidemic animals was shown due to pleiotropic mechanisms including the effect on airway hyperresponsiveness, lung inflammation, and oxidative stress.


1. Al-Shawwa B, Al-Huniti N, Titus G, Abu-Hasan M. Hypercholesterolemia is a potential risk factor for asthma. J Asthma 2006; 43(3):231-3.
2. Chen YC, Tung KY, Tsai CH, Su MW, Wang PC, Chen CH, et al. Lipid profiles in children with and without asthma: interaction of asthma and obesity on hyperlipidemia. Diabetes Metab Syndr 2013; 7(1):20-5.
3. Robertson AK, Zhou X, Strandvik B, Hansson G. Severe hypercholesterolaemia leads to strong Th2 responses to an exogenous antigen. Scand J Immunol 2004; 59(3):285-93.
4. Baldán Á, Gomes AV, Ping P, Edwards PA. Loss of ABCG1 results in chronic pulmonary inflammation. J Immunol 2008; 180(5):3560-8.
5. Yeh Y-F, Huang S-L. Enhancing effect of dietary cholesterol and inhibitory effect of pravastatin on allergic pulmonary inflammation. J Biomed Sci 2004; 11(5):599-606.
6. Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med 2011; 183(4):441-8.
7. McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004; 172(5):2903-8.
8. Fessler MB, Massing MW, Spruell B, Jaramillo R, Draper DW, Madenspacher JH, et al. Novel relationship of serum cholesterol with asthma and wheeze in the United States. J Allergy Clin Immunol 2009; 124(5):967-74.
9. Bradbury P, Traini D, Ammit AJ, Young PM, Ong HX. Repurposing of statins via inhalation to treat lung inflammatory conditions. Adv Drug Deliv Rev 2018; 133:93-106.
10. Yuan C, Zhou L, Cheng J, Zhang J, Teng Y, Huang M, et al. Statins as potential therapeutic drug for asthma? Respir Res 2012; 13(1):108.
11. Capra V, Rovati GE. Rosuvastatin inhibits human airway smooth muscle cells mitogenic response to eicosanoid contractile agents. Pulm Pharmacol Ther 2014; 27(1):10-6.
12. Olgun Yildizeli S, Kocakaya D, Balcan B, Ikinci A, Ahiskali R, Ceyhan B. Influence of rosuvastatin treatment on airway inflammatory markers and health related quality of life domains in asthmatic patients. Marmara Med J 2017; 30(2):73-81.
13. Kostapanos MS, Milionis HJ, Elisaf MS. An overview of the extra-lipid effects of rosuvastatin. J Cardiovasc Pharmacol Ther 2008; 13(3):157-74.
14. Tao Z, Zhang W, Wang D-x, Huang N-w, Hong B, Wang D, et al. Rosuvastatin attenuates mucus secretion in a murine model of chronic asthma by inhibiting the gamma-aminobutyric acid type A receptor. Chin Med J 2012; 125(8):1457-64.
15. O'Byrne PM, Inman MD. Airway hyperresponsiveness. Chest 2003; 123(3):411S-6S.
16. Palmer G, Chobaz V, Talabot‐Ayer D, Taylor S, So A, Gabay C, et al. Assessment of the efficacy of different statins in murine collagen‐induced arthritis. Arthritis Rheum 2004; 50(12):4051-9.
17. Kaleağasıoğlu F, Olcay E, Olgaç V. Statin-induced calcific Achilles tendinopathy in rats: comparison of biomechanical and histopathological effects of simvastatin, atorvastatin and rosuvastatin. Knee Surg Sports Traumatol Arthrosc 2017; 25(6):1884-91.
18. Alwahsh SM, Xu M, Schultze FC, Wilting J, Mihm S, Raddatz D, et al. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats. PloS one 2014; 9(8):e104220.
19. Shakeri F, Soukhtanloo M, Boskabady MH. The effect of hydro-ethanolic extract of Curcuma longa rhizome and curcumin on total and differential WBC and serum oxidant, antioxidant biomarkers in rat model of asthma. Iran J Basic Med Sci 2017; 20(2):155-65.
20. Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P, Sharma SK, et al. Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J Immunol 2008; 181(5):3540-8.
21. Saadat S, Mohammadi M, Fallahi M, Aslani MR. The protective effect of α-hederin, the active constituent of Nigella sativa, on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs. J Physiol Sci 2015; 65(3):285-92.
22. Ghosh S, Hoselton SA, Schuh JM. μ-Chain–Deficient Mice Possess B-1 Cells and Produce IgG and IgE, but Not IgA, following Systemic Sensitization and Inhalational Challenge in a Fungal Asthma Model. J Immunol 2012; 189(3):1322-9.
23. Boskabady MH, Ziaei T. Effect of ascorbic acid on airway responsiveness in ovalbumin sensitized guinea pigs. Respirology 2003; 8(4):473-8.
24. Saadat S, Beheshti F, Askari VR, Hosseini M, Mohammadian Roshan N, Boskabady MH. Aminoguanidine affects systemic and lung inflammation induced by lipopolysaccharide in rats. Respir Res 2019; 20(1):96.
25. Kianmeher M, Ghorani V, Boskabady MH. Animal model of asthma, various methods and measured parameters: a methodological review. Iran J Allergy Asthma Immunol 2017; 15(6):445-65.
26. Shakeri F, Boskabady MH. Anti-inflammatory, antioxidant, and immunomodulatory effects of curcumin in ovalbumin-sensitized rat. BioFactors 2017; 43(4):567-76.
27. Shakeri F, Roshan NM, Kaveh M, Eftekhar N, Boskabady MH. Curcumin affects tracheal responsiveness and lung pathology in asthmatic rats. Pharmacol Rep 2018; 70(5):981-7.
28. Scichilone N, Rizzo M, Benfante A, Catania R, Giglio RV, Nikolic D, et al. Serum low density lipoprotein subclasses in asthma. Respir Med 2013; 107(12):1866-72.
29. Aslani MR, Keyhanmanesh R, Alipour MR. Increased visfatin expression is associated with nuclear factor-κB in obese ovalbumin-sensitized male Wistar rat tracheae. Med Princ Pract 2017; 26(4):351-8.
30. Xu L, Dong X-w, Shen L-l, Li F-f, Jiang J-x, Cao R, et al. Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma. Int Immunopharmacol 2012; 12(4):556-64.
31. Ahmad T, Mabalirajan U, Sharma A, Aich J, Makhija L, Ghosh B, et al. Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma. Am J Respir Cell Mol Biol 2011; 44(4):531-9.
32. Zeki AA, Bratt JM, Chang KY, Franzi LM, Ott S, Silveria M, et al. Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung‐targeted approach to deliver statins. Physiol Rep 2015; 3(5).
33. Huang K-C, Chen C-W, Chen J-C, Lin W-W. HMG-CoA reductase inhibitors inhibit inducible nitric oxide synthase gene expression in macrophages. J Biomed Sci 2003; 10(4):396-405.
34. Kırzıoğlu F, Özmen Ö, Doğan B, Bulut M, Fentoğlu Ö, Özdem M. Effects of rosuvastatin on inducible nitric oxide synthase in rats with hyperlipidaemia and periodontitis. J Periodontal Res 2018; 53(2):258-66.
35. Ferreira TS, Lanzetti M, Barroso MV, Rueff-Barroso CR, Benjamim CF, de Brito-Gitirana L, et al. Oxidative stress and inflammation are differentially affected by atorvastatin, pravastatin, rosuvastatin, and simvastatin on lungs from mice exposed to cigarette smoke. Inflammation 2014; 37(5):1355-65.
36. Bast A, Weseler AR, Haenen GR, den Hartog GJ. Oxidative stress and antioxidants in interstitial lung disease. Curr Opin Pulm Med 2010; 16(5):516-20.
37. Dodiya H, Kale V, Goswami S, Sundar R, Jain M. Evaluation of adverse effects of lisinopril and rosuvastatin on hematological and biochemical analytes in wistar rats. Toxicol Int 2013; 20(2):170.
38. Brannan JD, Lougheed MD. Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment. Frontiers in physiology 2012; 3:460.
How to Cite
Saadat S, Mokhtari-Zaer A, Hadjzadeh M-A-R, Boskabady MH. Rosuvastatin Affects Tracheal Responsiveness, Bronchoalveolar Lavage Inflammatory Cells, and Oxidative Stress Markers in Hyperlipidemic and Asthmatic Rats. Iran J Allergy Asthma Immunol. :624-638.
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