Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Original article

Vol. 141 No. 4748 (2011)

Time-dependent inflammatory factor production and NFκB activation in a rodent model of intermittent hypoxia

  • S Li
  • X Qian
  • W Zhou
  • Y Zahng
  • J Feng
  • N Wan
  • Z Zhang
  • R Guo
  • B Chen
DOI
https://doi.org/10.4414/smw.2011.13309
Cite this as:
Swiss Med Wkly. 2011;141:w13309
Published
21.11.2011

Summary

OBJECTIVE: To study the systemic production of inflammatory factors and activation of transcription factor nuclear factor kappa B (NF-κB) in response to different levels of intermittent hypoxia and time.

METHODS: A total of 160 male Wistar rats were divided randomly into five groups. The first three groups were exposed to 5%, 7.5% and 10% intermittent hypoxia (referred to as IH-1, IH-2, and IH-3 respectively), the fourth group were subjected to 10% sustained hypoxia (abbreviated as SH), and the control group were exposed to normal oxygen (designated SC). At the second, fourth, sixth, and eighth week, eight rats in each group were sacrificed to collect serum. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum concentration of tumour necrosis factor alpha (TNF-α), interleukin-8 (IL-8), interleukin-6 (IL-6) and interleukin-10 (IL-10). Western blot was used to detect the protein levels of the phosphorylated NF-κB P65 in the nucleus of arterial endothelial cells.

RESULTS: In all three IH groups serum levels of TNF-α, IL-8 and IL-6 showed consecutive increment from onset to the 6th week under intermittent hypoxia; the levels of TNF-α and IL-8 dropped slightly on the 8th week, whereas those of IL-6 continued to increase. The levels of IL-10 decreased and reached nadir at the 6th week of intermittent hypoxia treatment. The inflammatory response was the most pronounced in the 6th week, at which time the TNF-α, IL-8 and IL-6 levels in IH groups were significantly higher than in the SC and SH group (F = 30.04, 11.77, 18.589; p <0.05). IL-10 levels were significantly lower than the SC and SH group (F = 10.403, p <0.05). Levels of TNF-α and IL-8 in the IH-1 group were significantly higher than those in the IH-3 group (F = 1.20, 34.68; p= 0.049, 0.046). Protein levels of phosphorylated NF-κB P65 in endothelial cells collected from thoracic aorta in all three IH groups were significantly higher than those in SC and SH groups (F = 63.136, p =0.01). A close correlation was identified between NF-κB p65 phosphorylation and the levels of TNF-α, IL-8, IL-6 and IL-10 (p = 0.01).

CONCLUSIONS:The inflammatory response, manifested by serum levels of inflammatory factors and nuclear accumulation of activated NF-κB P65, was more serious in the IH group than in the SH and control group, and was dependent on hypoxia levels. This reaction increased initially and then decreased, which indicates the presence of compensatory mechanisms and an adaptive response to such stressors in the body. Notably, the correlation of NFκB activation to production of inflammatory factors under intermittent hypoxia implies an important role of this transcription factor in inflammation-induced cardiovascular damage occurring during obstructive sleep apnoea (OSA), which has a typical breathing pattern of intermittent hypoxia.

References

  1. Roux F, D’Ambrosio C, Mohsenin V. Sleep-related breathing disorders and cardiovascular disease. Am J Med. 2000;108:396–402.
  2. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003;108:2317–22.
  3. Ozeren A, Aydin M, Tokac M, Demircan N, Unalacak M, Gurel A, et al. Levels of serum IL-1beta, IL-2, IL-8 and tumor necrosis factor-alpha in patients with unstable angina pectoris. Mediators Inflamm. 2003;12:361–5.
  4. Simonini A, Moscucci M, Muller DW, Bates ER, Pagani FD, Burdick MD, et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue. Circulation. 2000;101:1519–26.
  5. Chrysohoou C, Pitsavos C, Panagiotakos DB, Skoumas J, Stefanadis C. Association between prehypertension status and inflammatory markers related to atherosclerotic disease: The ATTICA Study. Am J Hypertens. 2004;17:568–73.
  6. Anguera I, Miranda-Guardiola F, Bosch X, Filella X, Sitges M, Marín JL, et al. Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and decreased risk of coronary events in patients with unstable angina. Am Heart J. 2002;144:811–7.
  7. Naya M, Tsukamoto T, Morita K, Katoh C, Furumoto T, Fujii S, et al. Plasma interleukin-6 and tumor necrosis factor-alpha Can predict coronary endothelial dysfunction in hypertensive patients. Hypertens Res. 2007;30:541–8.
  8. Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax. 2009;64:631–6.
  9. Tan Pei-Yi, Gao Wei-zhen, Kang Yi, Jiao Jian-jie, Lou Jian-shi, Liu Yan-xia. Culture and identification of endothelial cells from calf thoracic aorta in vitro. Journal of Tianjin Medical University. 2010;16(2):198–200.
  10. Liu SF, Malik AB. NF-kappaB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006;290:L622–45.
  11. Yamauchi M, Tamaki S, Tomoda K, Yoshikawa M, Fukuoka A, Makinodan K, et al. Evidence for activation of nuclear factor kappaB in obstructive sleep apnea. Sleep Breath. 2006;10:189–93.
  12. 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;126:1473–9.
  13. Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol. 2003;94:179–84.
  14. 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;107:1129–34.
  15. Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine. 2004;28:87–91.
  16. Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2006;174:824–30.
  17. Milleron O, Pillière R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J. 2004;25:728–34.
  18. Arias MA, García-Río F, Alonso-Fernández A, Mediano O, Martínez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function effects of nasal continuous positive airway pressure in men. Circulation. 2005;12:375–83.
  19. Alberti A, Sarchielli P, Gallinella E, Floridi A, Mazzotta G, Gallai V. Plasma cytokine levels in patients with obstructive sleep apnea syndrome: a preliminary study. J Sleep Res. 2003;12:305–11.
  20. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82:4196–200.
  21. Takahashi Y, Ganster RW, Gambotto A, Shao L, Kaizu T, Wu T, et al. Role of NF-kappaB on liver cold ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2002;283:G1175–84.
  22. de Martin R, Vanhove B, Cheng Q, Hofer E, Csizmadia V, Winkler H, et al. Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B. EMBO J. 1993;12:2773–9.
  23. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2(10):725–34.
  24. Oliver KM, Garvey JF, Ng CT, Veale DJ, Fearon U, Cummins EP, et al. Hypoxia activates NF-kappaB-dependent gene expression through the canonical signaling pathway. Antioxid Redox Signal. 2009;11(9):2057–64.
  25. Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stress response. Oncogene. 1999;18(45):6163–71.
  26. Williams A, Scharf SM. Obstructive sleep apnea, cardiovascular disease, and inflammation – is NF-kappaB the key? Sleep breath. 2007;11:69–76.
  27. Htoo AK, Greenberg H, Tongia S, Chen G, Henderson T, Wilson D, et al. Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation. Sleep Breath. 2006;10:43–50.
  28. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 2005;112:2660–7.