Skip to main content
SpringerLink
Log in

Protective Effect of Astragaloside IV Against Paraquat-Induced Lung Injury in Mice by Suppressing Rho Signaling

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The purpose of the present study was to evaluate the protective effects of astragaloside IV (AS IV) against paraquat (PQ)-induced pulmonary injury in vivo. Fifty BALB/C mice were randomized into five groups: (1) control, (2) PQ, (3) PQ + dexamethasone (Dex, 5 mg/kg), (4) PQ + AS IV (50 mg/kg), and (5) PQ + AS IV (100 mg/kg). A single dose of PQ (50 mg/kg, i.p.) was intraperitoneally given to induced acute lung injury. Then, mice were treated with AS IV (50 and 100 mg/kg/day, orally) for 5 days. At the end of the experiment, animals were euthanized; then, the bronchoalveolar lavage fluid (BALF) and lung tissues were collected for histological observation, biochemical assay, and Western blot analysis. Malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) in lung tissues, and interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α) levels in BALF were determined. Histological examination indicated that AS IV attenuated lung damage caused by PQ. Biochemical results showed that AS IV treatment significantly reduced the levels of MDA, MPO, and inflammatory cytokines while increased the levels of SOD, CAT, and GSH-Px compared with those in PQ group. Western blot results revealed that AS IV attenuated the Txnip/Trx expressions and inhibited Rho/ROCK/nuclear factor kappaB (NF-κB) signaling pathway in PQ-challenged mice. These findings suggested the protective effect of AS IV as a natural product on PQ-induced pulmonary injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Silva, R., H. Carmo, V. Vilas-Boas, D.J. Barbosa, M. Monteiro, P.G. de Pinho, et al. 2014. Several transport systems contribute to the intestinal uptake of Paraquat, modulating its cytotoxic effects. Toxicology Letters 232: 271–283.

    Article  PubMed  Google Scholar 

  2. Choi, J.S., S.S. Jou, M.H. Oh, Y.H. Kim, M.J. Park, H.W. Gil, et al. 2013. The dose of cyclophosphamide for treating paraquat-induced rat lung injury. The Korean Journal of Internal Medicine 28: 420–427.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Brennan, F.M., D. Chantry, A. Jackson, R. Maini, and M. Feldmann. 1989. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2: 244–247.

    Article  CAS  PubMed  Google Scholar 

  4. Jing, W., M. Chunhua, and W. Shumin. 2015. Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-kappaB pathway in vivo and in vitro. Toxicology and Applied Pharmacology 285: 128–135.

    Article  CAS  PubMed  Google Scholar 

  5. Hua, K., X. Sheng, T.T. Li, L.N. Wang, Y.H. Zhang, Z.J. Huang, et al. 2015. The edaravone and 3-n-butylphthalide ring-opening derivative 10b effectively attenuates cerebral ischemia injury in rats. Acta Pharmacologica Sinica 36: 917–927.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Gao, J., H. He, W. Jiang, X. Chang, L. Zhu, F. Luo, et al. 2015. Salidroside ameliorates cognitive impairment in a d-galactose-induced rat model of Alzheimer's disease. Behavioural Brain Research 293: 27–33.

    Article  CAS  PubMed  Google Scholar 

  7. Kim, S.J., and S.M. Lee. 2013. NLRP3 inflammasome activation in D-galactosamine and lipopolysaccharide-induced acute liver failure: role of heme oxygenase-1. Free Radical Biology & Medicine 65: 997–1004.

    Article  CAS  Google Scholar 

  8. Segain, J.P., D. Raingeard de la Bletiere, V. Sauzeau, A. Bourreille, G. Hilaret, C. Cario-Toumaniantz, et al. 2003. Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis. Gastroenterology 124: 1180–1187.

    Article  CAS  PubMed  Google Scholar 

  9. Santos, L.A., E.L. Ribeiro, K.P. Barbosa, I.T. Fragoso, F.O. Gomes, M.A. Donato, et al. 2014. Diethylcarbamazine inhibits NF-kappaB activation in acute lung injury induced by carrageenan in mice. International Immunopharmacology 23: 153–162.

    Article  CAS  PubMed  Google Scholar 

  10. Chen, T., J. Gao, P. Xiang, Y. Chen, J. Ji, P. Xie, et al. 2015. Protective effect of platycodin D on liver injury in alloxan-induced diabetic mice via regulation of Treg/Th17 balance. International Immunopharmacology 26: 338–348.

    Article  CAS  PubMed  Google Scholar 

  11. Chen, T., L. Xiao, L. Zhu, S. Ma, T. Yan, and H. Ji. 2015. Anti-asthmatic effects of ginsenoside rb1 in a mouse model of allergic asthma through relegating Th1/Th2. Inflammation 38(5): 1814–1822.

    Article  CAS  PubMed  Google Scholar 

  12. Ko, J.K., F.Y. Lam, and A.P. Cheung. 2005. Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis. World Journal of Gastroenterology 11: 5787–5794.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Zhang, W.J., P. Hufnagl, B.R. Binder, and J. Wojta. 2003. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression. Thrombosis and Haemostasis 90: 904–914.

    CAS  PubMed  Google Scholar 

  14. Luo, Y., Z. Qin, Z. Hong, X. Zhang, D. Ding, J.H. Fu, et al. 2004. Astragaloside IV protects against ischemic brain injury in a murine model of transient focal ischemia. Neuroscience Letters 363: 218–223.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, W.D., C. Zhang, X.H. Wang, P.J. Gao, D.L. Zhu, H. Chen, et al. 2006. Astragaloside IV dilates aortic vessels from normal and spontaneously hypertensive rats through endothelium-dependent and endothelium-independent ways. Planta Medica 72: 621–626.

    Article  CAS  PubMed  Google Scholar 

  16. Li, Z.P., and Q. Cao. 2002. Effects of astragaloside IV on myocardial calcium transport and cardiac function in ischemic rats. Acta Pharmacologica Sinica 23: 898–904.

    CAS  PubMed  Google Scholar 

  17. Nguyen, V., D.S. Malik, and M.A. Howland. 2014. Methylene blue protects against paraquat-induced acute lung injury in rats. International Immunopharmacology 20: 358.

    Article  CAS  PubMed  Google Scholar 

  18. Wang, J., Y.T. Liu, L. Xiao, L. Zhu, Q. Wang, and T. Yan. 2014. Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway. Inflammation 37: 2085–2090.

    Article  CAS  PubMed  Google Scholar 

  19. Chen, T., Y. Mou, J. Tan, L. Wei, Y. Qiao, T. Wei, et al. 2015. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. International Immunopharmacology 25: 55–64.

    Article  CAS  PubMed  Google Scholar 

  20. Li, W., Y.N. Sun, X.T. Yan, S.Y. Yang, S.B. Song, Y.M. Lee, et al. 2013. NF-kappaB inhibitory activity of sucrose fatty acid esters and related constituents from Astragalus membranaceus. Journal of Agricultural and Food Chemistry 61: 7081–7088.

    Article  CAS  PubMed  Google Scholar 

  21. Jin, H., Q. Luo, Y. Zheng, M. Nurahmat, J. Wu, B. Li, et al. 2013. CD4 + CD25 + Foxp3+ T cells contribute to the antiasthmatic effects of Astragalus membranaceus extract in a rat model of asthma. International Immunopharmacology 15: 42–49.

    Article  PubMed  Google Scholar 

  22. Tao, W., Q. Su, H. Wang, S. Guo, Y. Chen, J. Duan, et al. 2015. Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro. International Immunopharmacology 27: 138–147.

    Article  CAS  PubMed  Google Scholar 

  23. Lee, C.Y., J.J. Yang, S.S. Lee, C.J. Chen, Y.C. Huang, K.H. Huang, et al. 2014. Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin-induced acute lung injury via a JNK- and Akt-dependent NFkappaB pathway. Journal of Agricultural and Food Chemistry 62: 6337–6344.

    Article  CAS  PubMed  Google Scholar 

  24. Qian, J., Y. Ye, L. Lv, C. Zhu, and S. Ye. 2014. FTY720 attenuates paraquat-induced lung injury in mice. International Immunopharmacology 21: 426–431.

    Article  CAS  PubMed  Google Scholar 

  25. Huang, G.J., J.S. Deng, C.C. Chen, C.J. Huang, P.J. Sung, S.S. Huang, et al. 2014. Methanol extract of Antrodia camphorata protects against lipopolysaccharide-induced acute lung injury by suppressing NF-kappaB and MAPK pathways in mice. Journal of Agricultural and Food Chemistry 62: 5321–5329.

    Article  CAS  PubMed  Google Scholar 

  26. Lou, T., W. Jiang, D. Xu, T. Chen, and Y. Fu. 2015. Inhibitory effects of polydatin on lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation 38: 1213–1220.

    Article  CAS  PubMed  Google Scholar 

  27. Tianzhu, Z., Y. Shihai, and D. Juan. 2014. The effects of morin on lipopolysaccharide-induced acute lung injury by suppressing the lung NLRP3 inflammasome. Inflammation 37: 1976–1983.

    Article  PubMed  Google Scholar 

  28. Su, Z.Q., Z.Z. Mo, J.B. Liao, X.X. Feng, Y.Z. Liang, X. Zhang, et al. 2014. Usnic acid protects LPS-induced acute lung injury in mice through attenuating inflammatory responses and oxidative stress. International Immunopharmacology 22: 371–378.

    Article  CAS  PubMed  Google Scholar 

  29. Chen, L., L. Zhao, C. Zhang, and Z. Lan. 2014. Protective effect of p-cymene on lipopolysaccharide-induced acute lung injury in mice. Inflammation 37: 358–364.

    Article  CAS  PubMed  Google Scholar 

  30. Wang, Y.Z., Y.C. Zhang, J.S. Cheng, Q. Ni, P.W. Li, W. Han, et al. 2014. Protective effects of BML-111 on cerulein-induced acute pancreatitis-associated lung injury via activation of Nrf2/ARE signaling pathway. Inflammation 37: 1120–1133.

    Article  CAS  PubMed  Google Scholar 

  31. Xu, L., Y. Li, S. Wan, Y. Wang, and P. Yu. 2014. Protective effects of apocynin nitrone on acute lung injury induced by lipopolysaccharide in rats. International Immunopharmacology 20: 377–382.

    Article  CAS  PubMed  Google Scholar 

  32. Chen, Y., Y.C. Nie, Y.L. Luo, F. Lin, Y.F. Zheng, G.H. Cheng, et al. 2013. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food and Chemical Toxicology 58: 133–140.

    Article  CAS  PubMed  Google Scholar 

  33. Huang, X., Y. Liu, Y. Lu, and C. Ma. 2015. Anti-inflammatory effects of eugenol on lipopolysaccharide-induced inflammatory reaction in acute lung injury via regulating inflammation and redox status. International Immunopharmacology 26: 265–271.

    Article  CAS  PubMed  Google Scholar 

  34. Li, Y., J. Li, S. Li, Y. Li, X. Wang, B. Liu, et al. 2015. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicology and Applied Pharmacology 286: 53–63.

    Article  CAS  PubMed  Google Scholar 

  35. Spindel, O.N., C. World, and B.C. Berk. 2012. Thioredoxin interacting protein: redox dependent and independent regulatory mechanisms. Antioxidants & Redox Signaling 16: 587–596.

    Article  CAS  Google Scholar 

  36. Kelleher, Z.T., Y. Sha, M.W. Foster, W.M. Foster, M.T. Forrester, and H.E. Marshall. 2014. Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor kappaB (NF-kappaB) activation. The Journal of Biological Chemistry 289: 3066–3072.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Wong, C.M., L. Wei, S.L. Au, D.N. Fan, Y. Zhou, F.H. Tsang, et al. 2015. MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis. Oncotarget 6(15): 13658–13670.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Perey, A.C., I.M. Weishaar, and D.W. McGee. 2015. The effect of ROCK on TNF-alpha-induced CXCL8 secretion by intestinal epithelial cell lines is mediated through MKK4 and JNK signaling. Cellular Immunology 293: 80–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Shi, J., X. Wu, M. Surma, S. Vemula, L. Zhang, Y. Yang, et al. 2013. Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell death & Disease 4: e483.

    Article  CAS  Google Scholar 

  40. Kanno, S., S. Hirano, S. Chiba, H. Takeshita, T. Nagai, M. Takada, et al. 2015. The role of Rho-kinases in IL-1beta release through phagocytosis of fibrous particles in human monocytes. Archives of Toxicology 89: 73–85.

    Article  CAS  PubMed  Google Scholar 

  41. Yu, W.W., Z. Lu, H. Zhang, Y.H. Kang, Y. Mao, H.H. Wang, et al. 2014. Anti-inflammatory and protective properties of daphnetin in endotoxin-induced lung injury. Journal of Agricultural and Food Chemistry 62: 12315–12325.

    Article  CAS  PubMed  Google Scholar 

  42. Chen T, Guo Q, Wang H, Zhang H, Wang C, Zhang P, et al. 2015 Effects of esculetin on lipopolysaccharide(LPS)-induced acute lung injury via regulation of RhoA/Rho Kinase/NF-кB pathways in vivo and in vitro. Free Radical Research:1-21.

  43. Yeh, Y.H., Y.L. Hsieh, and Y.T. Lee. 2013. Effects of yam peel extract against carbon tetrachloride-induced hepatotoxicity in rats. Journal of Agricultural and Food Chemistry 61: 7387–7396.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants of the Natural Science Foundation of Jiangsu Province of China (BK20150707) and the Fundamental Research Funds for the Central Universities JKZD2013009 and ZJ15030). This Project also funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Research Innovation Program Project for Graduate Students in Jiangsu Province (CXZZ13_03), National Undergraduate Training Programs for Innovation and Entrepreneurship (G13034) and the Representational Achievement Cultivating Project of State Key Laboratory of Natural Medicines (SKLNMBZ201402).

Author information

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

    Tong Chen, Ruoning Wang, Wenjiao Jiang, Ang Xu, Guo Lu, Yi Ren, Yangmei Xu, Yangyang Song, Hui Ji & Zhanqiang Ma

  2. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Huimin Wang & Shoulei Yong

  3. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 210009, China

    Zhanqiang Ma

Authors
  1. Tong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruoning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenjiao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huimin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guo Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yi Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yangmei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yangyang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shoulei Yong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hui Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zhanqiang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hui Ji or Zhanqiang Ma.

Ethics declarations

Conflict of Interest

There is no conflict of interest among authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Wang, R., Jiang, W. et al. Protective Effect of Astragaloside IV Against Paraquat-Induced Lung Injury in Mice by Suppressing Rho Signaling. Inflammation 39, 483–492 (2016). https://doi.org/10.1007/s10753-015-0272-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0272-4

KEY WORDS

Search

Navigation