Tempol relieves lung injury in a rat model of chronic intermittent hypoxia via suppression of inflammation and oxidative stress

Document Type: Original Article

Authors

1 Department of Respiratory Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, People’s Republic of China

2 Department of Epidemiology and Biostatistics, School of Public Health, Kunming Medical University, Kunming, Yunnan 650500, People’s Republic of China

Abstract

Objective(s): Obstructive sleep apnea (OSA) is confirmed to cause lesions in multiple organs, especially in the lung tissue. Tempol is an antioxidant that has been reported to restrain inflammation and oxidative stress, with its role in OSA-induced lung injury being unclear. This study aimed to investigate the beneficial effect of tempol on chronic intermittent hypoxia (IH)-induced lung injury.
Materials and Methods: A rat model of OSA was established by IH. There were four groups: normal air (NA), IH, IH+tempol, NA+tempol. Inflammatory response was evaluated by TNF-α, IL-1β, and IL-6 levels. Oxidative stress was detected by MDA and GSH levels, and SOD activity. The protein levels were assessed by Western blot. DNA binding activity of NF-κB or Nrf2 was determined by electrophoretic mobility shift assay.
Results: According to the results, tempol administration alleviated pathological changes of the lung tissue, decreased leukocyte count and protein content (P<0.001) in bronchoalveolar lavage fluid (BALF). Inflammation response in lung tissue induced by IH was suppressed by tempol as evidenced by decreased levels of TNF-α, IL-1β, and IL-6 (P<0.001) and protein levels of COX-2 and iNOS (P<0.001). Moreover, tempol inhibited oxidative stress in lung tissue by down-regulating the MDA level (P<0.001) and enhancing SOD activity (P<0.001) and the GSH level (P<0.05). In addition, tempol repressed inflammation response via inactivation of the NF-κB pathway. Furthermore, the results suggested that tempol repressed oxidative stress by activating the Nrf2/HO-1 pathway.
Conclusion: Our findings suggest that tempol effectively relieves OSA-induced lung injury.

Keywords

Main Subjects


1. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5:136-143.
2. Lu W, Kang J, Hu K, Tang S, Zhou X, Yu S, et al. Angiotensin-(1-7) inhibits inflammation and oxidative stress to relieve lung injury induced by chronic intermittent hypoxia in rats. Braz J Med Biol Res 2016; 49:e5431.
3. Jun JC, Chopra S, Schwartz AR. Sleep apnoea. Eur Respir Rev 2016; 25:12-18.
4. Dylag AM, Mayer CA, Raffay TM, Martin RJ, Jafri A, MacFarlane PM. Long-term effects of recurrent intermittent hypoxia and hyperoxia on respiratory system mechanics in neonatal mice. Pediatr Res 2017; 81:565-571.
5. Zhang J, Zheng L, Cao J, Chen B, Jin D. Inflammation induced by increased frequency of intermittent hypoxia is attenuated by tempol administration. Braz J Med Biol Res 2015; 48:1115-1121.
6. Skelly JR, Edge D, Shortt CM, Jones JF, Bradford A, O’Halloran KD. Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia. Am J Respir Cell Mol Biol 2012; 46:139-148.
7. Troncoso Brindeiro CM, da Silva AQ, Allahdadi KJ, Youngblood V, Kanagy NL. Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. Am J Physiol Heart Circ Physiol 2007; 293:H2971-2976.
8. Guo H, Cao J, Li J, Yang X, Jiang J, Feng J, et al. Lymphocytes from intermittent hypoxia-exposed rats increase the apoptotic signals in endothelial cells via oxidative and inflammatory injury in vitro. Sleep Breath 2015; 19:969-976.
9. Ramond A, Godin-Ribuot D, Ribuot C, Totoson P, Koritchneva I, Cachot S, et al. Oxidative stress mediates cardiac infarction aggravation induced by intermittent hypoxia. Fundam Clin Pharmacol 2013; 27:252-261.
10. Liu Y, Li Y, Li N, Teng W, Wang M, Zhang Y, et al. TGF-beta1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21. Sci Rep 2016; 6:32231.
11. Wang TY, Zhou QL, Li M, Shang YX. Shikonin alleviates allergic airway remodeling by inhibiting the ERK-NF-kappaB signaling pathway. Int Immunopharmacol 2017; 48:169-179.
12. Zhao H, Zhao M, Wang Y, Li F, Zhang Z. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats. J Histochem Cytochem 2016; 64:125-137.
13. El-Sayed NS, Mahran LG, Khattab MM. Tempol, a membrane-permeable radical scavenger, ameliorates lipopolysaccharide-induced acute lung injury in mice: a key role for superoxide anion. Eur J Pharmacol 2011; 663:68-73.
14. Teke Z, Kabay B, Ozden A, Yenisey C, Bir F, Demirkan NC, et al. Effects of tempol, a membrane-permeable radical scavenger, on local and remote organ injuries caused by intestinal ischemia/reperfusion in rats. J Surg Res 2008; 149:259-271.
15. Cuzzocrea S, McDonald MC, Mazzon E, Filipe HM, Centorrino T, Lepore V, et al. Beneficial effects of tempol, a membrane-permeable radical scavenger, on the multiple organ failure induced by zymosan in the rat. Crit Care Med 2001; 29:102-111.
16. Wang Y, Chai Y, He X, Ai L, Sun X, Huang Y, et al. Intermittent hypoxia simulating obstructive sleep apnea causes pulmonary inflammation and activates the Nrf2/HO-1 pathway. Exp Ther Med 2017; 14:3463-3470.
17. Zhao C, Sun J, Fang C, Tang F. 1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice. Inflammation 2014; 37:566-572.
18. Minoguchi K, Tazaki T, Yokoe T, Minoguchi H, Watanabe Y, Yamamoto M, et al. Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 2004; 126:1473-1479.
19. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003; 107:1129-1134.
20. Mehra R, Storfer-Isser A, Kirchner HL, Johnson N, Jenny N, Tracy RP, et al. Soluble interleukin 6 receptor: A novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med 2006; 166:1725-1731.
21. Copray JC, Mantingh I, Brouwer N, Biber K, Kust BM, Liem RS, et al. Expression of interleukin-1 beta in rat dorsal root ganglia. J Neuroimmunol 2001; 118:203-211.
22. Kleinert H, Pautz A, Linker K, Schwarz PM. Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 2004; 500:255-266.
23. Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 2003; 54:469-487.
24. Chen Q, Wang N, Zhu M, Lu J, Zhong H, Xue X, et al. TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: A proteomic and metabolomic insight. Redox Biol 2017; 15:266-276.
25. Lu W, Kang J, Hu K, Tang S, Zhou X, Yu S, et al. Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis. Braz J Med Biol Res 2017; 50:e5594.
26. Chen TI, Chen MY. Zinc Is Indispensable in Exercise-Induced Cardioprotection against Intermittent Hypoxia-Induced Left Ventricular Function Impairment in Rats. PLoS One 2016; 11:e0168600.
27. Zhao YN, Wang HY, Li JM, Chen BY, Xia G, Zhang PP, et al. Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome. Mol Med Rep 2016; 13:137-145.
28. Hou YJ, Zhao YY, Xiong B, Cui XS, Kim NH, Xu YX, et al. Mycotoxin-containing diet causes oxidative stress in the mouse. PLoS One 2013; 8:e60374.
29. Valko M, Jomova K, Rhodes CJ, Kuca K, Musilek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 2016; 90:1-37.
30. Rhee JW, Lee KW, Kim D, Lee Y, Jeon OH, Kwon HJ, et al. NF-kappaB-dependent regulation of matrix metalloproteinase-9 gene expression by lipopolysaccharide in a macrophage cell line RAW 264.7. J Biochem Mol Biol 2007; 40:88-94.
31. Wang SS, Purdue MP, Cerhan JR, Zheng T, Menashe I, Armstrong BK, et al. Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk. PLoS One 2009; 4:e5360.
32. Yan F, Chen Y, Azat R, Zheng X. Mulberry Anthocyanin Extract Ameliorates Oxidative Damage in HepG2 Cells and Prolongs the Lifespan of Caenorhabditis elegans through MAPK and Nrf2 Pathways. Oxid Med Cell Longev 2017; 2017:7956158.
33. Lee MS, Lee B, Park KE, Utsuki T, Shin T, Oh CW, et al. Dieckol enhances the expression of antioxidant and detoxifying enzymes by the activation of Nrf2-MAPK signalling pathway in HepG2 cells. Food Chem 2015; 174:538-546.
34. Li CG, Ni CL, Yang M, Tang YZ, Li Z, Zhu YJ, et al. Honokiol protects pancreatic beta cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo. Biomed Pharmacother 2018; 97:1229-1237.