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p-Synephrine suppresses lipopolysaccharide-induced acute lung injury by inhibition of the NF-κB signaling pathway

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Abstract

Objective

We investigated whether p-synephrine exerts potent anti-inflammatory effects against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we further investigated the inhibitory mechanism of p-synephrine in LPS-induced ALI.

Methods

Lipopolysaccharide (0.5 mg/kg) was instilled intranasally in phosphate-buffered saline to induce acute lung injury, and 6, 24, and 48 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro-inflammatory mediator. We also evaluated the effects of p-synephrine on LPS-induced the severity of pulmonary injury. The phosphorylation of nuclear factor-κB (NF-κB) p65 protein was analyzed by Western blotting.

Results

Our data showed that p-synephrine significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, reactive oxygen species, myeloperoxidase activity and enhanced superoxide dismutase (SOD) in mice with LPS-induced ALI. Tumor necrosis factor α and interleukin (IL)-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after p-synephrine pretreatment. In addition, p-synephrine suppressed not only the phosphorylation of NF-κB but also the degradation of its inhibitor (IκBα).

Conclusions

These results suggested that the inhibition of NF-κB activation and the regulation of SOD are involved in the mechanism of p-synephrine’s protection against ALI.

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References

  1. Zhu T, Zhang W, Wang DX. Insulin up-regulates epithelial sodium channel in LPS-induced acute lung injury model in rats by SGK1 activation. Injury. 2012;43:1277–83.

    Article  PubMed  Google Scholar 

  2. Deng J, Wang DX, Deng W, Li CY, Tong J, Ma H. Regulation of alveolar fluid clearance and ENaC expression in lung by exogenous angiotensin II. Respir Physiol Neurobiol. 2012;181:53–61.

    Article  CAS  PubMed  Google Scholar 

  3. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.

    Article  CAS  PubMed  Google Scholar 

  4. Brigham KL, Meyrick B. Endotoxin and lung injury. Am Rev Respir Dis. 1986;133:913–27.

    CAS  PubMed  Google Scholar 

  5. Kim TH, Yoon HJ, Lim CM, Kim EK, Kim MJ, Koh Y. The role of endogenous histamine on the pathogenesis of the lipopolysaccharide (LPS)-induced acute lung injury: a pilot study. Inflammation. 2005;29:72–80.

    Article  CAS  PubMed  Google Scholar 

  6. Venaille TJ, Ryan G, Robinson BW. Epithelial cell damage is induced by neutrophil-derived, not pseudomonas-derived, proteases in cystic fibrosis sputum. Respir Med. 1998;92:233–40.

    Article  CAS  PubMed  Google Scholar 

  7. Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev. 2001;53:135–59.

    CAS  PubMed  Google Scholar 

  8. Liu SF, Malik AB. NF-κB activation as a pathologic mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006;290:L622–45.

    Article  CAS  PubMed  Google Scholar 

  9. Everhart MB, Han W, Sherrill TP, Arutiunov M, Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS. Duration and Intensity of NF-κB activity determine the severity of endotoxin induced acute lung injury. J Immunol. 2006;176:4995–5005.

    Article  CAS  PubMed  Google Scholar 

  10. Moine P, McIntyre R, Schwartz MD, Kaneko D, Shenkar R, Le Tulzo Y, Moore EE, Abraham E. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome. Shock. 2000;13:85–91.

    Article  CAS  PubMed  Google Scholar 

  11. Liu S, Feng G, Wang GL, Liu GJ. p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol. 2008;14:159–65.

    Article  CAS  Google Scholar 

  12. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87:13–20.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu T, Wang DX, Zhang W, Liao XQ, Guan X, Bo H, Sun JY, Huang NW, He J, Zhang YK, Tong J, Li CY. Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-κB. PLoS ONE. 2013;8(2):e56407. doi:10.1371/journal.pone.0056407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Yang W, Qiang D, Zhang M, Ma L, Zhang Y, Qing C, Xu Y, Zhen C, Liu J, Chen YH. Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models. Int Immunopharmacol. 2011;11:683–92.

    Article  CAS  PubMed  Google Scholar 

  15. Dwyer JT, Allison DB, Coates PM. Dietary supplements in weight reduction. J Am Diet Assoc. 2005;105:S80–6.

    Article  CAS  PubMed  Google Scholar 

  16. Brunton L, Lazo J, Parker K. In: Goodman G, editor. The pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2005.

    Google Scholar 

  17. Moro CO, Basile G. Obesity and medicinal plants. Fitoterapia. 2000;71:S73–82.

    Article  PubMed  Google Scholar 

  18. Shi Q, Liu Z, Yang Y, Geng P, Zhu YY, Zhang Q, Bai F, Bai G. Identification of anti-asthmatic compounds in Pericarpium citri reticulatae and evaluation of their synergistic effects. Acta Pharmacol Sin. 2009;30(5):567–75.

    Article  CAS  PubMed  Google Scholar 

  19. Ko HC, Wang YH, Liou KT, Chen CM, Chen CH, Wang WY, Chang S, Hou YC, Chen KT, Chen CF, Shen YC. Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. Eur J Pharmacol. 2007;555:211–7.

    Article  CAS  PubMed  Google Scholar 

  20. Vaschetto R, Kuiper JW, Chiang SR, Haitsma JJ, Juco JW, Uhlig S, Plotz FB, Corte FD, Zhang H, Slutsky AS. Inhibition of poly(adenosine diphosphateribose) polymerase attenuates ventilator-induced lung injury. Anesthesiology. 2008;108:261–8.

    Article  CAS  PubMed  Google Scholar 

  21. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011;21:103–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Gonzalez PK, Zhuang J, Doctrow SR, Malfroy B, Benson PF, Menconi MJ, Fink MP. Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury. Shock. 1996;6:S23–6.

    Article  PubMed  Google Scholar 

  23. Tanaka T, Grusby MJ, Kaisho T. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nat Immunol. 2007;8:584–91.

    Article  CAS  PubMed  Google Scholar 

  24. Yang J, Qu JM, Summah H, Zhang J, Zhu YG, Jiang HN. Protective effects of imipramine in murine endotoxin-induced acute lung injury. Eur J Pharmacol. 2010;638:128–33.

    Article  CAS  PubMed  Google Scholar 

  25. Rubenfeld GD. Epidemiology of acute lung injury. Crit Care Med. 2003;31:S276–84.

    Article  PubMed  Google Scholar 

  26. Zhang XM, Song KJ, Xiong HZ, Li HY, Chu X, Deng XM. Protective effect of florfenicol on acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 2009;9:1525–9.

    Article  CAS  PubMed  Google Scholar 

  27. Joshua AS, Arabinda D, Swapan KR, Naren LB. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87:10–20.

    Article  Google Scholar 

  28. Lin Y, Zhu X, Yao WZ, Yang YL, A LT, Chen L. Yohimbine protects against endotoxininduced acute lung injury by blockade of alpha 2A adrenergic receptor in rats. Chin Med J (Engl). 2011;124(7):1069–74.

  29. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–56.

    Article  CAS  PubMed  Google Scholar 

  30. Giebelen IA, van Westerloo DJ, LaRosa GJ, de Vos AF, van der Poll T. Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung. Shock. 2007;28:700–3.

    CAS  PubMed  Google Scholar 

  31. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–12.

    Article  CAS  PubMed  Google Scholar 

  32. Martin TR. Lung cytokines and ARDS: Roger S. Mitchell Lecture. Chest. 1999;116:2S–8S.

    Article  CAS  PubMed  Google Scholar 

  33. Shang Y, Xu SP, Wu Y, Jiang YX, Wu ZY, Yuan SY, Yao SL. Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J. 2009;122:1388–93.

    CAS  PubMed  Google Scholar 

  34. Mecklenburgh K, Murray J, Brazil T, Ward C, Rossi AG, Chilvers ER. Role of neutrophil apoptosis in the resolution of pulmonary inflammation. Monaldi Arch Chest Dis. 1999;54:345–9.

    CAS  PubMed  Google Scholar 

  35. Cavaillon JM, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit Care Med. 2005;33:S506–9.

    Article  PubMed  Google Scholar 

  36. Johansson MW, Patarroyo M, Oberg F, Siegbahn A, Nilson K. Myeloperoxidase mediates cell adhesion via the alpha M beta 2 integrin (Mac-1, CD11b/CD18). J Cell Sci. 1997;110:1133–9.

    CAS  PubMed  Google Scholar 

  37. Zhang XZ, Li JH, Chen C, Ci XX, Yu QL, Zhang XC, Deng XM. Protective effect of abamectin on acute lung injury induced by lipopolysaccharide in mice. Fundam Clin Pharmacol. 2011;25(6):700–7.

    Article  CAS  PubMed  Google Scholar 

  38. El-Benna J, Dang PM, Gougerot-Pocidalo MA, Elbim C. Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Archivum Immunologiae et Therapia Experimentalis. 2005;53:199–206.

    CAS  Google Scholar 

  39. Manca D, Ricard AC, Trottier B, Chevalier G. Studies on lipid peroxidation in rat tissues following administration of low and moderate doses of cadmium chloride. Toxicology. 1991;67:303–23.

    Article  CAS  PubMed  Google Scholar 

  40. Ward PA. Oxidative stress: acute and progressive lung injury. Ann N Y Acad Sci. 2010;1203:53–9.

    Article  CAS  PubMed  Google Scholar 

  41. Kinnula VL, Crapo JD. Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med. 2003;167:1600–19.

    Article  PubMed  Google Scholar 

  42. Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. Int Immunopharmacol. 2002;2(11):1509–20.

    Article  CAS  PubMed  Google Scholar 

  43. Kang JL, Lee HW, Lee HS, Pack IS, Chong Y, Castranova V, Koh Y. Genistein prevents nuclear factor-kappa B activation and acute lung injury induced by lipopolysaccharide. Am J Respir Crit Care Med. 2001;164:2206–12.

    Article  CAS  PubMed  Google Scholar 

  44. Xia YF, Ye BQ, Li YD, Wang JG, He XJ, Lin X, Yao X, Ma D, Slungaard A, Hebbel RP, Key NS, Geng JG. Andrographolide attenuates inflammation by inhibition of NF-κB activation through covalent modification of reduced cysteine 62 of p50. J Immunol. 2004;173:4207–17.

    Article  CAS  PubMed  Google Scholar 

  45. Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.

    Article  CAS  PubMed  Google Scholar 

  46. Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol. 2002;10:725–34.

    Article  Google Scholar 

  47. Lin FY, Chen YH, Chen YL, Wu TC, Li CY, Chen JW, Lin SJ. Ginkgo biloba extract inhibits endotoxin-induced human aortic smooth muscle cell proliferation via suppression of toll-like receptor 4 expression and NADPH oxidase activation. J Agric Food Chem. 2007;55:1977–84.

    Article  CAS  PubMed  Google Scholar 

  48. Takei H, Hirabuki M, Yoshizaki F. Analysis of synephrine in the peel of citrus fruit, immature citrus fruit and decoctions of Chinese medicinal prescriptions containing these crude drugs by capillary electrophoresis. Anal Sci. 1999;15:1017–20.

    Article  CAS  Google Scholar 

  49. Rabe KF, Schmidt DT. Pharmacological treatment of asthma today. Eur Respir J Suppl. 2001;34:34s–40s.

    Article  CAS  PubMed  Google Scholar 

  50. Parmar HS, Kar A. Medicinal values of fruit peels from Citrus sisensis, Punica granatum, and Musa paradisiacal with respect to alterations in tissue lipid peroxidation and serum concentration of glucose, insulin, and thyroid hormones. J Med Food. 2008;11(2):376–81.

    Article  CAS  PubMed  Google Scholar 

  51. Parmar HS, Kar A. Antiperoxidative, antithyroidal, antihyperglycemic and cardioprotective role of Citrus sinensis peel extract in male mice. Phytother Res. 2008;22(6):791–5.

    Article  CAS  PubMed  Google Scholar 

  52. Arch JR. β3-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol. 2002;440(2–3):99–107.

    Article  CAS  PubMed  Google Scholar 

  53. Oana F, Homma T, Takeda H, Matsuzawa A, Akahane S, Isaji M, Akahane M. DNA microarray analysis of white adipose tissue from obese (fa/fa) Zucker rats treated with a β3-adrenoceptor agonist, KTO-7924. Pharmacol Res. 2005;52(5):395–400.

    Article  CAS  PubMed  Google Scholar 

  54. Arbo MD, Schmitt GC, Limberger MF, Charão MF, Moro AM, Ribeiro GL, Dallegrave E, Garcia SC, Leal MB, Limberger RP. Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Regul Toxicol Pharmacol. 2009;54(2):114–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Nature Science Foundation of China (no. 31172172).

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Authors and Affiliations

  1. Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin, 130062, People’s Republic of China

    Qianchao Wu, Lanan Wassy Soromou, Na Chen, Beibei Li & Haihua Feng

  2. Institute of Infectious Diseases, 302 Hospital of People’s Liberation Army, 100, the 4th Ring Road, Beijing, 100039, People’s Republic of China

    Ruisheng Li

  3. Collage of Animal Science and Technology, Inner Mongolia National University, Tongliao, 028042, People’s Republic of China

    Xue Yuan & Guoquan Sun

  4. Institut Supérieur des Sciences et de Médecine Vétérinaire (ISSMV) de Dalaba, Dalaba, Republic of Guinea

    Lanan Wassy Soromou

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  1. Qianchao Wu
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Correspondence to Haihua Feng.

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Q. Wu and R. Li contributed equally to this work.

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Wu, Q., Li, R., Soromou, L.W. et al. p-Synephrine suppresses lipopolysaccharide-induced acute lung injury by inhibition of the NF-κB signaling pathway. Inflamm. Res. 63, 429–439 (2014). https://doi.org/10.1007/s00011-014-0715-7

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  • DOI: https://doi.org/10.1007/s00011-014-0715-7

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