Skip to main content
Log in

Pseudoginsenoside-F11 Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Neutrophil Infiltration and Accelerating Neutrophil Clearance

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

Abstract

Pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, has been reported to have anti-inflammatory properties, but the effects of PF11 on acute lung inflammation were unknown. The present study aimed to investigate the protective effects and potential mechanisms of PF11 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in male BALB/c mice. After being treated with PF11 (3, 10, and 30 mg/kg, intravenous) once a day for 3 consecutive days, the mice were challenged by intratracheal instillation of LPS, and then their lung tissues and bronchoalveolar lavage fluid (BALF) were collected for further analysis. The results showed that PF11 attenuated LPS-induced ALI, with alleviated histopathological damage, decreased lung wet/dry weight ratio, and reduced protein concentration and inflammatory cells number in BALF. Moreover, PF11 reversed the LPS-induced increases of mRNA expression and protein levels of interleukin-6, tumor necrosis factor-α, and interleukin-1β. Meanwhile, PF11 decreased LPS-induced myeloperoxidase activity and neutrophil infiltration in lung tissue by reducing the expression of macrophage inflammatory protein-2 and intercellular adhesion molecule-1, as well as enhanced neutrophil clearance by accelerating neutrophils apoptosis and their phagocytosis by alveolar macrophages. In conclusion, these results indicated that PF11 significantly attenuated LPS-induced ALI through suppressing neutrophil infiltration and accelerating neutrophil clearance, suggesting its potential in the treatment of ALI.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Grommes, J., and O. Soehnlein. 2011. Contribution of neutrophils to acute lung injury. Molecular Medicine 17 (3–4): 293–307.

    Article  CAS  PubMed  Google Scholar 

  2. Lin, S., H. Wu, C. Wang, Z. Xiao, and F. Xu. 2018. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Frontiers in Immunology 9: 1545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Villar, J., D. Sulemanji, and R.M. Kacmarek. 2014. The acute respiratory distress syndrome: incidence and mortality, has it changed? Current Opinion in Critical Care 20 (1): 3–9.

    Article  PubMed  Google Scholar 

  4. Kumar, V., and A. Sharma. 2010. Neutrophils: Cinderella of innate immune system. International Immunopharmacology 10 (11): 1325–1334.

    Article  CAS  PubMed  Google Scholar 

  5. Petri, B., and M.J. Sanz. 2018. Neutrophil chemotaxis. Cell and Tissue Research 371 (3): 425–436.

    Article  CAS  PubMed  Google Scholar 

  6. Yuan, Q., Y.W. Jiang, T.T. Ma, Q.H. Fang, and L. Pan. 2014. Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats. Journal of Inflammation 11 (1): 40.

    Article  CAS  PubMed  Google Scholar 

  7. Downey, G.P., Q. Dong, J. Kruger, S. Dedhar, and V. Cherapanov. 1999. Regulation of neutrophil activation in acute lung injury. Chest 116 (1 Suppl): 46s–54s.

    Article  CAS  PubMed  Google Scholar 

  8. Takano, T., N. Azuma, M. Satoh, A. Toda, Y. Hashida, R. Satoh, and T. Hohdatsu. 2009. Neutrophil survival factors (TNF-alpha, GM-CSF, and G-CSF) produced by macrophages in cats infected with feline infectious peritonitis virus contribute to the pathogenesis of granulomatous lesions. Archives of Virology 154 (5): 775–781.

    Article  CAS  PubMed  Google Scholar 

  9. Lee, W.L., and G.P. Downey. 2001. Neutrophil activation and acute lung injury. Current Opinion in Critical Care 7 (1): 1–7.

    Article  CAS  PubMed  Google Scholar 

  10. Fotouhi-Ardakani, N., D.E. Kebir, N. Pierre-Charles, L. Wang, S.P. Ahern, J.G. Filep, and E. Milot. 2010. Role for myeloid nuclear differentiation antigen in the regulation of neutrophil apoptosis during sepsis. American Journal of Respiratory and Critical Care Medicine 182 (3): 341–350.

    Article  CAS  PubMed  Google Scholar 

  11. Kennedy, A.D., and F.R. DeLeo. 2009. Neutrophil apoptosis and the resolution of infection. Immunologic Research 43 (1–3): 25–61.

    Article  PubMed  Google Scholar 

  12. Voll, R.E., M. Herrmann, E.A. Roth, C. Stach, J.R. Kalden, and I. Girkontaite. 1997. Immunosuppressive effects of apoptotic cells. Nature 390 (6658): 350–351.

    Article  CAS  PubMed  Google Scholar 

  13. Wang, Z.J., L. Sun, W. Peng, S. Ma, C. Zhu, F. Fu, and T. Heinbockel. 2011. Ginseng derivative ocotillol enhances neuronal activity through increased glutamate release: a possible mechanism underlying increased spontaneous locomotor activity of mice. Neuroscience 195: 1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, C.M., M.Y. Liu, F. Wang, M.J. Wei, S. Wang, C.F. Wu, and J.Y. Yang. 2013. Anti-amnesic effect of pseudoginsenoside-F11 in two mouse models of Alzheimer’s disease. Pharmacology, Biochemistry and Behavior 106: 57–67.

    Article  CAS  PubMed  Google Scholar 

  15. Wang, J.Y., J.Y. Yang, F. Wang, S.Y. Fu, Y. Hou, B. Jiang, J. Ma, C. Song, and C.F. Wu. 2013. Neuroprotective effect of pseudoginsenoside-f11 on a rat model of Parkinson’s disease induced by 6-hydroxydopamine. Evidence-based Complementary and Alternative Medicine 2013: 152798.

    PubMed  PubMed Central  Google Scholar 

  16. Liu, Y.Y., T.Y. Zhang, X. Xue, D.M. Liu, H.T. Zhang, L.L. Yuan, Y.L. Liu, H.L. Yang, S.B. Sun, C. Zhang, H.S. Xu, C.F. Wu, and J.Y. Yang. 2017. Pseudoginsenoside-F11 attenuates cerebral ischemic injury by alleviating autophagic/lysosomal defects. CNS Neuroscience & Therapeutics 23 (7): 567–579.

    Article  CAS  Google Scholar 

  17. Wu, C.F., Y.L. Liu, M. Song, W. Liu, J.H. Wang, X. Li, and J.Y. Yang. 2003. Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice. Pharmacology, Biochemistry and Behavior 76 (1): 103–109.

    Article  CAS  PubMed  Google Scholar 

  18. Wang, X., C. Wang, J. Wang, S. Zhao, K. Zhang, J. Wang, W. Zhang, C. Wu, and J. Yang. 2014. Pseudoginsenoside-F11 (PF11) exerts anti-neuroinflammatory effects on LPS-activated microglial cells by inhibiting TLR4-mediated TAK1/IKK/NF-kappaB, MAPKs and Akt signaling pathways. Neuropharmacology 79: 642–656.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Z., H. Yang, J. Yang, J. Xie, J. Xu, C. Liu, and C. Wu. 2019. Pseudoginsenoside-F11 attenuates cognitive impairment by ameliorating oxidative stress and neuroinflammation in d-galactose-treated mice. International Immunopharmacology 67: 78–86.

    Article  CAS  PubMed  Google Scholar 

  20. Xu, Y.Y., Y.Y. Zhang, Y.Y. Ou, X.X. Lu, L.Y. Pan, H. Li, Y. Lu, and D.F. Chen. 2015. Houttuyniacordata Thunb. polysaccharides ameliorates lipopolysaccharide-induced acute lung injury in mice. Journal of Ethnopharmacology 173: 81–90.

    Article  CAS  PubMed  Google Scholar 

  21. Barreto, T.R., C. Costola-de-Souza, R.O. Margatho, N. Queiroz-Hazarbassanov, S.C. Rodrigues, L.F. Felicio, J. Palermo-Neto, and A. Zager. 2018. Repeated Domperidone treatment modulates pulmonary cytokines in LPS-induced acute lung injury in mice. International Immunopharmacology 56: 43–50.

    Article  CAS  PubMed  Google Scholar 

  22. Wu, F., W. Shi, G. Zhou, H. Yao, C. Xu, W. Xiao, J. Wu, and X. Wu. 2016. Ginkgolide B functions as a determinant constituent of Ginkgolides in alleviating lipopolysaccharide-induced lung injury. Biomedicine and Pharmacotherapy 81: 71–78.

    Article  CAS  PubMed  Google Scholar 

  23. Gong, J., H. Liu, J. Wu, H. Qi, Z.Y. Wu, H.Q. Shu, H.B. Li, L. Chen, Y.X. Wang, B. Li, M. Tang, Y.D. Ji, S.Y. Yuan, S.L. Yao, and Y. Shang. 2015. Maresin 1 prevents lipopolysaccharide-induced neutrophil survival and accelerates resolution of acute lung injury. Shock 44 (4): 371–380.

    Article  CAS  PubMed  Google Scholar 

  24. Xu, Y.N., Z. Zhang, P. Ma, and S.H. Zhang. 2011. Adenovirus-delivered angiopoietin 1 accelerates the resolution of inflammation of acute endotoxic lung injury in mice. Anesthesia and Analgesia 112 (6): 1403–1410.

    Article  PubMed  Google Scholar 

  25. Schwab, J.M., N. Chiang, M. Arita, and C.N. Serhan. 2007. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447 (7146): 869–874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Miller, S.I., R.K. Ernst, and M.W. Bader. 2005. LPS, TLR4 and infectious disease diversity. Nature Reviews Microbiology 3 (1): 36–46.

    Article  CAS  PubMed  Google Scholar 

  27. D’Alessio, F.R. 2018. Mouse models of acute lung injury and ARDS. Methods in Molecular Biology 1809: 341–350.

    Article  CAS  PubMed  Google Scholar 

  28. Chen, H., C. Bai, and X. Wang. 2010. The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Review of Respiratory Medicine 4 (6): 773–783.

    Article  CAS  PubMed  Google Scholar 

  29. Zhao, D., J. Zhang, G. Xu, and Q. Wang. 2017. Artesunate protects LPS-induced acute lung injury by inhibiting TLR4 expression and inducing Nrf2 activation. Inflammation 40 (3): 798–805.

    Article  CAS  PubMed  Google Scholar 

  30. Huang, X., H. Xiu, S. Zhang, and G. Zhang. 2018. The role of macrophages in the pathogenesis of ALI/ARDS. Mediators of Inflammation 2018: 1264913.

    PubMed  PubMed Central  Google Scholar 

  31. Madjdpour, C., B. Oertli, U. Ziegler, J.M. Bonvini, T. Pasch, and B. Beck-Schimmer. 2000. Lipopolysaccharide induces functional ICAM-1 expression in rat alveolar epithelial cells in vitro. American Journal of Physiology. Lung Cellular and Molecular Physiology 278 (3): L572–L579.

    Article  CAS  PubMed  Google Scholar 

  32. Yu, M.L., and A.H. Limper. 1997. Pneumocystis carinii induces ICAM-1 expression in lung epithelial cells through a TNF-alpha-mediated mechanism. American Journal of Physiology 273 (6): L1103–L1111.

    CAS  PubMed  Google Scholar 

  33. Pugin, J., B. Ricou, K.P. Steinberg, P.M. Suter, and T.R. Martin. 1996. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. American Journal of Respiratory and Critical Care Medicine 153 (6 Pt 1): 1850–1856.

    Article  CAS  PubMed  Google Scholar 

  34. Zhou, X., Q. Dai, and X. Huang. 2012. Neutrophils in acute lung injury. Frontiers in Bioscience (Landmark Ed) 17: 2278–2283.

    Article  CAS  Google Scholar 

  35. Butt, Y., A. Kurdowska, and T.C. Allen. 2016. Acute lung injury: a clinical and molecular review. Archives of Pathology and Laboratory Medicine 140 (4): 345–350.

    Article  CAS  PubMed  Google Scholar 

  36. Laffey, J.G., and M.A. Matthay. 2017. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value. American Journal of Respiratory and Critical Care Medicine 196 (3): 266–273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou, B., G. Weng, Z. Huang, T. Liu, and F. Dai. 2018. Arctiin prevents LPS-induced acute lung injury via inhibition of PI3K/AKT signaling pathway in mice. Inflammation 41 (6): 2129–2135.

    Article  CAS  PubMed  Google Scholar 

  38. Wan, L., D. Meng, H. Wang, S. Wan, S. Jiang, S. Huang, L. Wei, and P. Yu. 2018. Preventive and therapeutic effects of thymol in a lipopolysaccharide-induced acute lung injury mice model. Inflammation 41 (1): 183–192.

    Article  CAS  PubMed  Google Scholar 

  39. Gonzalez-Lopez, A., and G.M. Albaiceta. 2012. Repair after acute lung injury: molecular mechanisms and therapeutic opportunities. Critical Care (London, England) 16 (2): 209.

    Article  Google Scholar 

  40. Matthay, M.A., L.B. Ware, and G.A. Zimmerman. 2012. The acute respiratory distress syndrome. Journal of Clinical Investigation 122 (8): 2731–2740.

    Article  CAS  PubMed  Google Scholar 

  41. Goodman, R.B., J. Pugin, J.S. Lee, and M.A. Matthay. 2003. Cytokine-mediated inflammation in acute lung injury. Cytokine and Growth Factor Reviews 14 (6): 523–535.

    Article  CAS  PubMed  Google Scholar 

  42. Chollet-Martin, S., B. Jourdain, C. Gibert, C. Elbim, J. Chastre, and M.A. Gougerot-Pocidalo. 1996. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. American Journal of Respiratory and Critical Care Medicine 154 (3 Pt 1): 594–601.

    Article  CAS  PubMed  Google Scholar 

  43. Prince, L.R., L. Allen, E.C. Jones, P.G. Hellewell, S.K. Dower, M.K. Whyte, and I. Sabroe. 2004. The role of interleukin-1beta in direct and toll-like receptor 4-mediated neutrophil activation and survival. American Journal of Pathology 165 (5): 1819–1826.

    Article  CAS  PubMed  Google Scholar 

  44. Park, W.Y., R.B. Goodman, K.P. Steinberg, J.T. Ruzinski, F. Radella 2nd, D.R. Park, J. Pugin, S.J. Skerrett, L.D. Hudson, and T.R. Martin. 2001. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 164 (10 Pt 1): 1896–1903.

    Article  CAS  PubMed  Google Scholar 

  45. Sharp, C., A.B. Millar, and A.R. Medford. 2015. Advances in understanding of the pathogenesis of acute respiratory distress syndrome. Respiration 89 (5): 420–434.

    Article  CAS  PubMed  Google Scholar 

  46. Geerts, L., P.G. Jorens, J. Willems, M. De Ley, and H. Slegers. 2001. Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Critical Care Medicine 29 (10): 1920–1924.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng, Z., and L. Li. 2016. Ginsenoside Rg3 ameliorates lipopolysaccharide-induced acute lung injury in mice through inactivating the nuclear factor-kappaB (NF-kappaB) signaling pathway. International Immunopharmacology 34: 53–59.

    Article  CAS  PubMed  Google Scholar 

  48. Zhu, T., D.X. Wang, W. Zhang, X.Q. Liao, X. Guan, H. Bo, J.Y. Sun, N.W. Huang, J. He, Y.K. Zhang, J. Tong, and C.Y. Li. 2013. Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-kappaB. PLoS One 8 (2): e56407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Williams, A.E., and R.C. Chambers. 2014. The mercurial nature of neutrophils: still an enigma in ARDS? American Journal of Physiology. Lung Cellular and Molecular Physiology 306 (3): L217–L230.

    Article  CAS  PubMed  Google Scholar 

  50. Sakamoto, S., T. Okanoue, Y. Itoh, K. Sakamoto, K. Nishioji, Y. Nakagawa, N. Yoshida, T. Yoshikawa, and K. Kashima. 1997. Intercellular adhesion molecule-1 and CD18 are involved in neutrophil adhesion and its cytotoxicity to cultured sinusoidal endothelial cells in rats. Hepatology 26 (3): 658–663.

    Article  CAS  PubMed  Google Scholar 

  51. El Kebir, D., and J.G. Filep. 2013. Targeting neutrophil apoptosis for enhancing the resolution of inflammation. Cells 2 (2): 330–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Croasdell, A., P.F. Duffney, N. Kim, S.H. Lacy, P.J. Sime, and R.P. Phipps. 2015. PPARgamma and the innate immune system mediate the resolution of inflammation. PPAR Research 2015: 549691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cox, G., J. Crossley, and Z. Xing. 1995. Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo. American Journal of Respiratory Cell and Molecular Biology 12 (2): 232–237.

    Article  CAS  PubMed  Google Scholar 

  54. Rydell-Tormanen, K., L. Uller, and J.S. Erjefalt. 2006. Direct evidence of secondary necrosis of neutrophils during intense lung inflammation. European Respiratory Journal 28 (2): 268–274.

    Article  CAS  PubMed  Google Scholar 

  55. Tian, B.P., L.X. Xia, Z.Q. Bao, H. Zhang, Z.W. Xu, Y.Y. Mao, C. Cao, L.Q. Che, J.K. Liu, W. Li, Z.H. Chen, S. Ying, and H.H. Shen. 2017. Bcl-2 inhibitors reduce steroid-insensitive airway inflammation. Journal of Allergy and Clinical Immunology 140 (2): 418–430.

    Article  CAS  PubMed  Google Scholar 

  56. Karin, M., and Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-[kappa] B activity. Annual Review of Immunology 18: 621–663.

    Article  CAS  PubMed  Google Scholar 

  57. Karin, M. 1999. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. Journal of Biological Chemistry 274 (39): 27339–27342.

    Article  CAS  PubMed  Google Scholar 

  58. Cai, L., Z. Wang, J.M. Meyer, A. Ji, and D.R. van der Westhuyzen. 2012. Macrophage SR-BI regulates LPS-induced pro-inflammatory signaling in mice and isolated macrophages. Journal of Lipid Research 53 (8): 1472–1481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Blackwell, T.S., and J.W. Christman. 1997. The role of nuclear factor-kappa B in cytokine gene regulation. American Journal of Respiratory Cell and Molecular Biology 17 (1): 3–9.

    Article  CAS  PubMed  Google Scholar 

  60. De Plaen, I.G., X.B. Han, X. Liu, W. Hsueh, S. Ghosh, and M.J. May. 2006. Lipopolysaccharide induces CXCL2/macrophage inflammatory protein-2 gene expression in enterocytes via NF-kappaB activation: independence from endogenous TNF-alpha and platelet-activating factor. Immunology 118 (2): 153–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Doerschuk, C.M., J.P. Mizgerd, H. Kubo, L. Qin, and T. Kumasaka. 1999. Adhesion molecules and cellular biomechanical changes in acute lung injury: Giles F. Filley Lecture. Chest 116 (1 Suppl): 37s–43s.

    Article  CAS  PubMed  Google Scholar 

  62. Manning, A.M., F.P. Bell, C.L. Rosenbloom, J.G. Chosay, C.A. Simmons, J.L. Northrup, R.J. Shebuski, C.J. Dunn, and D.C. Anderson. 1995. NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. Journal of Inflammation 45 (4): 283–296.

    CAS  PubMed  Google Scholar 

  63. Sun, Z., S. Dragon, A. Becker, and A.S. Gounni. 2013. Leptin inhibits neutrophil apoptosis in children via ERK/NF-kappaB-dependent pathways. PLoS One 8 (1): e55249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, Z., N. Chen, J.B. Liu, J.B. Wu, J. Zhang, Y. Zhang, and X. Jiang. 2014. Protective effect of resveratrol against acute lung injury induced by lipopolysaccharide via inhibiting the myd88-dependent Toll-like receptor 4 signaling pathway. Molecular Medicine Reports 10 (1): 101–106.

    Article  CAS  PubMed  Google Scholar 

  65. Sabroe, I., E.C. Jones, L.R. Usher, M.K. Whyte, and S.K. Dower. 2002. Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses. Journal of Immunology 168 (9): 4701–4710.

    Article  CAS  Google Scholar 

  66. Poon, I.K., C.D. Lucas, A.G. Rossi, and K.S. Ravichandran. 2014. Apoptotic cell clearance: basic biology and therapeutic potential. Nature Reviews. Immunology 14 (3): 166–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mingyi Zhao or Jingyu Yang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Statement

All experimental procedures were approved by the Ethics Committee of Shenyang Pharmaceutical University, and followed the guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, P., Hou, Y., Zhang, W. et al. Pseudoginsenoside-F11 Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Neutrophil Infiltration and Accelerating Neutrophil Clearance. Inflammation 42, 1857–1868 (2019). https://doi.org/10.1007/s10753-019-01047-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01047-5

KEY WORDS

Navigation