Sevoflurane Prevents Airway Remodeling via Downregulation of VEGF and TGF-β1 in Mice with OVA-Induced Chronic Airway Inflammation

Abstract

Asthma is characterized by chronic airway inflammation, which is the underlying cause of airway remodeling featured by goblet cell hyperplasia, subepithelial fibrosis, and proliferation of smooth muscle. Sevoflurane has been used to treat life-threatening asthma and our previous study shows that sevoflurane inhibits acute lung inflammation in ovalbumin (OVA)-induced allergic mice. However, the effect of sevoflurane on airway remodeling in the context of chronic airway inflammation and the underlying mechanism are still unknown. Here, female C57BL/6 mice were used to establish chronic airway inflammation model. Hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Sirius red (SR) staining were used to evaluate airway remodeling. Protein levels of α-SMA, VEGF, and TGF-β1 in lung tissues were detected by western blotting analyses and immunohistochemistry staining. Results showed that inhalation of sevoflurane inhibited chronic airway inflammation including inflammatory cell infiltration and pro-inflammatory cytokine production in BALF of the OVA-challenged mice. Meanwhile, sevoflurane suppressed airway thickening, goblet cell hyperplasia, smooth muscle hyperplasia, collagen deposition, and fiber hyperplasia in the lung tissues of the mice with airway remodeling. Most notably, sevoflurane inhibited the OVA-induced expressions of VEGF and TGF-β1. These results suggested that sevoflurane effectively inhibits airway remodeling in mouse model of chronic airway inflammation, which may be due to the downregulation of VEGF and TGF-β1in lung tissues. Therefore, our results indicate a potential role of sevoflurane in inhibiting airway remodeling besides its known suppression effect on airway inflammation, and support the use of sevoflurane in treating severe asthma in ICU.

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

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

References

  1. 1.

    Galli, S.J., M. Tsai, and A.M. Piliponsky. 2008. The development of allergic inflammation. Nature 454 (7203): 445–454.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Girodet, P.O., A. Ozier, I. Bara, J.M. Tunon de Lara, R. Marthan, and P. Berger. 2011. Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention. Pharmacology & Therapeutics 130 (3): 325–337.

    CAS  Article  Google Scholar 

  3. 3.

    Trejo Bittar, H.E., S.A. Yousem, and S.E. Wenzel. 2015. Pathobiology of severe asthma. Annual Review of Pathology 10: 511–545.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Durrani, S.R., R.K. Viswanathan, and W.W. Busse. 2011. What effect does asthma treatment have on airway remodeling? Current perspectives. The Journal of Allergy and Clinical Immunology 128 (3): 439–448 quiz 449-450.

    PubMed  Article  Google Scholar 

  5. 5.

    Doherty, T.A., P. Soroosh, N. Khorram, S. Fukuyama, P. Rosenthal, J.Y. Cho, P.S. Norris, H. Choi, S. Scheu, K. Pfeffer, B.L. Zuraw, C.F. Ware, D.H. Broide, and M. Croft. 2011. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nature Medicine 17 (5): 596–603.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Robinson, C.B., J. Leonard, and R.A. Panettieri Jr. 2012. Drug development for severe asthma: what are the metrics? Pharmacology & Therapeutics 135 (2): 176–181.

    CAS  Article  Google Scholar 

  7. 7.

    Leatherman, J. 2015. Mechanical ventilation for severe asthma. Chest 147 (6): 1671–1680.

    PubMed  Article  Google Scholar 

  8. 8.

    Louie, S., B.M. Morrissey, N.J. Kenyon, T.E. Albertson, and M. Avdalovic. 2012. The critically ill asthmatic--from ICU to discharge. Clinical Reviews in Allergy and Immunology 43 (1–2): 30–44.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Carrie, S., and T.A. Anderson. 2015. Volatile anesthetics for status asthmaticus in pediatric patients: a comprehensive review and case series. Paediatric Anaesthesia 25 (5): 460–467.

    PubMed  Article  Google Scholar 

  10. 10.

    Watanabe, K., T. Mizutani, S. Yamashita, Y. Tatekawa, T. Jinbo, and M. Tanaka. 2008. Prolonged sevoflurane inhalation therapy for status asthmaticus in an infant. Paediatric Anaesthesia 18 (6): 543–545.

    PubMed  Article  Google Scholar 

  11. 11.

    Weber, T., C. Schiebenpflug, and E. Deusch. 2012. Inhalational sevoflurane in severe bronchial obstruction unresponsive to multipharmacologic therapy: a case report. F1000Res 1: 56.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Schultz, T.E. 2005. Sevoflurane administration in status asthmaticus: a case report. AANA Journal 73 (1): 35–36.

    PubMed  Google Scholar 

  13. 13.

    Lin, T.Y., N. Venkatesan, M. Nishioka, S. Kyoh, L. Al-Alwan, C.J. Baglole, D.H. Eidelman, M.S. Ludwig, and Q. Hamid. 2014. Monocyte-derived fibrocytes induce an inflammatory phenotype in airway smooth muscle cells. Clinical and Experimental Allergy 44 (11): 1347–1360.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Royce, S.G., Y. Moodley, and C.S. Samuel. 2014. Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis. Pharmacology & Therapeutics 141 (3): 250–260.

    CAS  Article  Google Scholar 

  15. 15.

    Burburan, S.M., J.D. Silva, S.C. Abreu, C.S. Samary, I.H. Guimaraes, D.G. Xisto, M.M. Morales, and P.R. Rocco. 2014. Effects of inhalational anaesthetics in experimental allergic asthma. Anaesthesia 69 (6): 573–582.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Shen, Q.Y., L. Fang, H.M. Wu, F. He, P.S. Ding, and R.Y. Liu. 2015. Repeated inhalation of sevoflurane inhibits airway inflammation in an OVA-induced mouse model of allergic airway inflammation. Respirology 20 (2): 258–263.

    PubMed  Article  Google Scholar 

  17. 17.

    Doherty, T., and D. Broide. 2007. Cytokines and growth factors in airway remodeling in asthma. Current Opinion in Immunology 19 (6): 676–680.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Ricciardolo, F.L., F. Sabatini, V. Sorbello, S. Benedetto, I. Defilippi, L. Petecchia, C. Usai, et al. 2013. Expression of vascular remodelling markers in relation to bradykinin receptors in asthma and COPD. Thorax 68 (9): 803–811.

    PubMed  Article  Google Scholar 

  19. 19.

    Wisniewski, J.A., and L. Borish. 2011. Novel cytokines and cytokine-producing T cells in allergic disorders. Allergy and Asthma Proceedings 32 (2): 83–94.

    CAS  Article  Google Scholar 

  20. 20.

    Keglowich, L.F., and P. Borger. 2015. The three A’s in asthma - airway smooth muscle, airway remodeling & angiogenesis. Open Respiratory Medicine Journal 9: 70–80.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kumar, R.K., C. Herbert, and P.S. Foster. 2008. The “classical” ovalbumin challenge model of asthma in mice. Current Drug Targets 9 (6): 485–494.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Wu, H.M., Q.Y. Shen, L. Fang, S.H. Zhang, P.T. Shen, Y.J. Liu, and R.Y. Liu. 2016. JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis. Journal of Pineal Research 60 (4): 415–423.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Lopez-Guisa, J.M., C. Powers, D. File, E. Cochrane, N. Jimenez, and J.S. Debley. 2012. Airway epithelial cells from asthmatic children differentially express proremodeling factors. The Journal of Allergy and Clinical Immunology 129 (4): 990–997 e996.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Yuksel, H., O. Yilmaz, M. Karaman, H.A. Bagriyanik, F. Firinci, M. Kiray, A. Turkeli, and O. Karaman. 2013. Role of vascular endothelial growth factor antagonism on airway remodeling in asthma. Annals of Allergy, Asthma & Immunology 110 (3): 150–155.

    CAS  Article  Google Scholar 

  25. 25.

    Wang, N., D. Yan, Y. Liu, X. Gu, J. Sun, F. Long, and S. Jiang. 2016. A HuR/TGF-beta1 feedback circuit regulates airway remodeling in airway smooth muscle cells. Respiratory Research 17 (1): 117.

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Puig, N.R., P. Ferrero, M.L. Bay, G. Hidalgo, J. Valenti, N. Amerio, and G. Elena. 2002. Effects of sevoflurane general anesthesia: immunological studies in mice. International Immunopharmacology 2 (1): 95–104.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Burburan, S.M., D.G. Xisto, H.C. Ferreira, R. Riva Ddos, G.M. Carvalho, W.A. Zin, and P.R. Rocco. 2007. Lung mechanics and histology during sevoflurane anesthesia in a model of chronic allergic asthma. Anesthesia and Analgesia 104 (3): 631–637.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Wicks, J., H.M. Haitchi, S.T. Holgate, D.E. Davies, and R.M. Powell. 2006. Enhanced upregulation of smooth muscle related transcripts by TGF beta2 in asthmatic (myo) fibroblasts. Thorax 61 (4): 313–319.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Ierodiakonou, D., D.S. Postma, G.H. Koppelman, J. Gerritsen, N.H. ten Hacken, W. Timens, H.M. Boezen, and J.M. Vonk. 2013. TGF-beta1 polymorphisms and asthma severity, airway inflammation, and remodeling. The Journal of Allergy and Clinical Immunology 131 (2): 582–585.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Bakakos, P., G. Patentalakis, and A. Papi. 2016. Vascular biomarkers in asthma and COPD. Current Topics in Medicinal Chemistry 16 (14): 1599–1609.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Yang, Y.C., N. Zhang, K. Van Crombruggen, G.H. Hu, S.L. Hong, and C. Bachert. 2012. Transforming growth factor-beta1 in inflammatory airway disease: a key for understanding inflammation and remodeling. Allergy 67 (10): 1193–1202.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Rogerio, A.P., C. Fontanari, E. Borducchi, A.C. Keller, M. Russo, E.G. Soares, D.A. Albuquerque, and L.H. Faccioli. 2008. Anti-inflammatory effects of Lafoensia pacari and ellagic acid in a murine model of asthma. European Journal of Pharmacology 580 (1–2): 262–270.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Bordon, Y. 2013. Asthma and allergy: TGFbeta--too much of a good thing? Nature Reviews. Immunology 13 (9): 618–619.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Liu, Y.N., W.J. Zha, Y. Ma, F.F. Chen, W. Zhu, A. Ge, X.N. Zeng, and M. Huang. 2015. Galangin attenuates airway remodelling by inhibiting TGF-beta1-mediated ROS generation and MAPK/Akt phosphorylation in asthma. Scientific Reports 5: 11758.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Firszt, R., D. Francisco, T.D. Church, J.M. Thomas, J.L. Ingram, and M. Kraft. 2014. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-beta1 in airway fibroblasts in asthma. The European Respiratory Journal 43 (2): 464–473.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Minagawa, S., J. Lou, R.I. Seed, A. Cormier, S. Wu, Y. Cheng, L. Murray, et al. 2014. Selective targeting of TGF-beta activation to treat fibroinflammatory airway disease. Science Translational Medicine 6 (241): 241ra279.

    Article  Google Scholar 

  37. 37.

    Ribatti, D., I. Puxeddu, E. Crivellato, B. Nico, A. Vacca, and F. Levi-Schaffer. 2009. Angiogenesis in asthma. Clinical and Experimental Allergy 39 (12): 1815–1821.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Harkness, L.M., A.W. Ashton, and J.K. Burgess. 2015. Asthma is not only an airway disease, but also a vascular disease. Pharmacology & Therapeutics 148: 17–33.

    CAS  Article  Google Scholar 

  39. 39.

    Takyar, S., H. Vasavada, J.G. Zhang, F. Ahangari, N. Niu, Q. Liu, C.G. Lee, L. Cohn, and J.A. Elias. 2013. VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis. The Journal of Experimental Medicine 210 (10): 1993–2010.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Simpson, A., A. Custovic, R. Tepper, P. Graves, D.A. Stern, M. Jones, J. Hankinson, J.A. Curtin, J. Wu, M. Blekic, B.K. Bukvic, N. Aberle, S. Marinho, D. Belgrave, W.J. Morgan, and F.D. Martinez. 2012. Genetic variation in vascular endothelial growth factor-a and lung function. American Journal of Respiratory and Critical Care Medicine 185 (11): 1197–1204.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Funding

This study was supported by the Natural Science Foundation of China (no. 81770032) and Natural Science Foundation of Anhui Province (no. 1708085QH173).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Qi-Ying Shen or Hui-Mei Wu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All animal experiments described in this study were approved by the Animal Care and Use Committee of Anhui Medical University.

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

Verify currency and authenticity via CrossMark

Cite this article

Shen, Q., Wu, L., Wei, C. et al. Sevoflurane Prevents Airway Remodeling via Downregulation of VEGF and TGF-β1 in Mice with OVA-Induced Chronic Airway Inflammation. Inflammation 42, 1015–1022 (2019). https://doi.org/10.1007/s10753-019-00963-w

Download citation

KEY WORDS

  • asthma
  • airway inflammation
  • sevoflurane
  • airway remodeling