Skip to main content

Advertisement

SpringerLink
Log in

Aquaporin 4 Blockade Attenuates Acute Lung Injury Through Inhibition of Th17 Cell Proliferation in Mice

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Acute lung injury (ALI) is a syndrome characterized by damage to the alveolar-capillary wall, pulmonary edema and recruitment of inflammatory cells. Previous studies have indicated that aquaporin 4 (AQP4) plays a key role in brain edema formation and resolution. However, the role of AQP4 in the development and progression of ALI is not clear and needs to be resolved. In our current study, mouse ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) at a concentration of 30 mg/kg. For the inhibition of AQP4, 200 mg/kg of TGN-020 (Sigma, USA) was administered intraperitoneally every 6 h starting at 30 min before intratracheal instillation of LPS. The results of the present work indicate, for the first time, that mice treated with the AQP4 inhibitor TGN-020 had attenuated LPS-induced lung injury, reduced proinflammatory cytokine release (including IL-1α, IL-1β, IL-6, TNF-α, IL-23, and IL-17A), and an improved survival rate. Additionally, we found that the attenuated lung injury scores, increased survival rate, and decreased BALF total protein concentration in TGN-020-treated mice were all abrogated by rIL-17A administration. Furthermore, TGN-020 treatment downregulated the phosphorylation of PI3K and Akt, increased the expression of SOCS3, and decreased the expression of p-STAT3 and RORγt. In conclusion, inhibition of AQP4 by TGN-020 has a detectable protective effect against lung tissue injury induced by LPS, and this effect is associated with inhibition of IL-17A through the downregulation of the PI3K/Akt signaling pathway and upregulation of SOCS3 protein.

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

Similar content being viewed by others

References

  1. Sheu, C.C., M.N. Gong, R. Zhai, F. Chen, E.K. Bajwa, P.F. Clardy, D.C. Gallagher, B.T. Thompson, and D.C. Christiani. 2010. Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS. Chest. 138: 559–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cooke, C.R., C.V. Shah, R. Gallop, S. Bellamy, M. Ancukiewicz, M.D. Eisner, P.N. Lanken, A.R. Localio, and J.D. Christie. 2009. A simple clinical predictive index for objective estimates of mortality in acute lung injury. Critical Care Medicine 37: 1913–1920.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zemans, R.L., and M.A. Matthay. 2004. Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury. Critical Care 8: 469–477.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Verkman, Alan S., Marc O. Anderson, and Marios C. Papadopoulos. 2014. Aquaporins: important but elusive drug targets. Nature Reviews. Drug Discovery 13 (4): 259–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Verschuur, C.V., A.J. Kooi, and D. Troost. 2015. Anti-aquaporin 4 related paraneoplastic neuromyelitis optica in the presence of adenocarcinoma of the lung. Clinical Neuropathology 34: 232–236.

    Article  PubMed  Google Scholar 

  7. Sorani, M.D. 2008. Novel variants in human aquaporin-4 reduce cellular water permeability. Human Molecular Genetics 17 (15): 2379–2389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Verkman, A.S. 2013. Biology of AQP4 and anti-AQP4 antibody: therapeutic implications. Brain Pathology 23 (6): 684–695.

    Article  CAS  PubMed  Google Scholar 

  9. Bloch, O., and G.T. Manley. 2007. The role of aquaporin-4 in cerebral water transport and edema. Neurosurgical Focus, Neurosurg. Focus. 22: E3.

    PubMed  Google Scholar 

  10. Papadopoulos, M.C., and A.S. Verkman. 2007. Aquaporin-4 and brain edema. Pediatric Nephrology 22 (6): 778–784.

    Article  PubMed  Google Scholar 

  11. Xiong, L.L., Y. Tan, H.Y. Ma, P. Dai, Y.X. Qin, R.A. Yang, Y.Y. Xu, Z. Deng, W. Zhao, Q.J. Xia, T.H. Wang, and Y.H. Zhang. 2016. Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. International Immunopharmacology 38: 54–60.

    Article  CAS  PubMed  Google Scholar 

  12. Li, Y., H. Lu, X. Lv, Q. Tang, W. Li, H. Zhu, and Y. Long. 2018. Blockade of aquaporin 4 inhibits irradiation-induced pulmonary inflammation and modulates macrophage polarization in mice. Inflammation. 41 (6): 2196–2205.

    Article  CAS  PubMed  Google Scholar 

  13. McFarland, H.F., and R. Martin. 2007. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunology 8: 913–919.

    Article  CAS  PubMed  Google Scholar 

  14. Wu, M.P., Y.S. Zhang, Q.M. Zhou, J. Xiong, Y.R. Dong, and C. Yan. 2016. Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway. Pharmacological Research 104: 115–123.

    Article  CAS  PubMed  Google Scholar 

  15. Wang, L., T. Wang, H. Li, Q. Liu, Z. Zhang, W. Xie, Y. Feng, T. Socorburam, G. Wu, Z. Xia, and Q. Wu. 2016. Receptor interacting protein 3- mediated necroptosis promotes lipopolysaccharide-induced inflammation and acute respiratory distress syndrome in mice. PLoS One 11 (5): e0155723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ayasoufi, K., N. Kohei, M. Nicosia, et al. 2018. Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia. American Journal of Transplantation 00: 1–9.

    Google Scholar 

  17. Yang, B.L., F. Chen, L.J. Xu, J.H. Xing, and X.F. Wang. 2017. HMGB1-TLR4-IL23-IL17A axis promotes paraquat-induced acute lung injury by mediating neutrophil infiltration in mice. Scientific Reports 7: 597.

    Article  CAS  Google Scholar 

  18. Liao, Y.H., N. Xia, S.F. Zhou, T.T. Tang, and X.X. Yan. 2012. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. Journal of the American College of Cardiology 59 (4): 420–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, Y.H., H.L. Fu, M.L. Tian, Y.Q. Wang, W. Chen, L.L. Cai, X.H. Zhou, and H.B. Yuan. 2016. Neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice. Scientific Reports 6: 19869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, W., Z. Zhou, L. Li, C.Q. Zhong, X. Zheng, X. Wu, Y. Zhang, H. Ma, D. Huang, W. Li, Z. Xia, and J. Han. 2013. Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. The Journal of Biological Chemistry 288 (23): 16247–16261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, W., V. Jadhav, J. Tang, and J.H. Zhang. 2008. HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model. Neurobiology 31: 433–441.

    CAS  Google Scholar 

  22. Bhargava, M., and C.H. Wendt. 2012. Biomarkers in acute lung injury. Translational Research 159 (4): 205–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Han, J., C.Q. Zhong, and D.W. Zhang. 2011. Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nature Immunology 12 (12): 1143–1149.

    Article  CAS  PubMed  Google Scholar 

  24. Chignard, M., and V. Balloy. 2000. Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide. American Journal of Physiology. Lung Cellular and Molecular Physiology 279 (6): L1083–L1090.

    Article  CAS  PubMed  Google Scholar 

  25. Kantrow, S.P., Z. Shen, T. Jagneaux, P. Zhang, and S. Nelson. 2009. Neutrophil-mediated lung permeability and host defense proteins. American Journal of Physiology. Lung Cellular and Molecular Physiology 297 (4): L738–L745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Risso, K., et al. 2005. Early infectious acute respiratory distress syndrome is characterized by activation and proliferation of alveolar T-cells. European Journal of Clinical Microbiology & Infectious Diseases 34: 1111–1118.

    Article  CAS  Google Scholar 

  27. Yan, Z., Z. Xiaoyu, S. Zhixin, Q. di, D. Xinyu, X. Jing, H. Jing, D. Wang, Z. Xi, Z. Chunrong, and W. Daoxin. 2016. Rapamycin attenuates acute lung injury induced by LPS through inhibition of Th17 cell proliferation in mice. Scientific Reports 6: 20156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu, Z.X., M.S. Ji, J. Yan, Y. Cai, J. Liu, H.F. Yang, Y. Li, Z.C. Jin, and J.X. Zheng. 2015. The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Critical Care 19: 82.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dai, H., L. Xu, Y. Tang, Z. Liu, and T. Sun. 2015. Treatment with a neutralising anti-rat interleukin-17 antibody after multiple-trauma reduces lung inflammation. Injury. 46 (8): 1465–1470.

    Article  PubMed  Google Scholar 

  30. Kluger, M.A., A. Nosko, T. Ramcke, B. Goerke, M.C. Meyer, C. Wegscheid, M. Luig, G. Tiegs, R.A.K. Stahl, and O.M. Steinmetz. 2017. RORγt expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses. Clinical and Experimental Immunology 188 (1): 63–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Marone, R., V. Cmiljanovic, B. Giese, and M.P. Wymann. 2008. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochimica et Biophysica Acta 1784: 159–185.

    Article  CAS  PubMed  Google Scholar 

  32. Osaka, D., Y. Shibata, K. Kanouchi, M. Nishiwaki, T. Kimura, H. Kishi, S. Abe, S. Inoue, Y. Tokairin, A. Igarashi, K. Yamauchi, Y. Aida, T. Nemoto, K. Nunomiya, K. Fukuzaki, and I. Kubota. 2011. Soluble endothelial selectin in acute lung injury complicated by severe pneumonia. International Journal of Medical Sciences 8: 302–308.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Seki, H., K. Fukunaga, M. Arita, H. Arai, H. Nakanishi, R. Taguchi, T. Miyasho, R. Takamiya, K. Asano, A. Ishizaka, J. Takeda, and B.D. Levy. 2010. The anti-inflammatory and proresolving mediator resolvin E1 protects rat from bacterial pneumonia and acute lung injury. Journal of Immunology 184: 836–843.

    Article  CAS  Google Scholar 

  34. Nieuwenhuizen, L., P.G. de Groot, J.C. Grutters, and D.H. Biesma. 2009. A review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia. European Journal of Haematology 82: 413–425.

    Article  CAS  PubMed  Google Scholar 

  35. Curtis, M.M., and S.S. Way. 2009. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 126: 177–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, J.T., A.C. Melton, G. Su, D.E. Hamm, M. LaFemina, J. Howard, X. Fang, S. Bhat, K.M. Huynh, C.M. O’Kane, R.J. Ingram, R.R. Muir, D.F. McAuley, M.A. Matthay, and D. Sheppard. 2015. Unexpected role for adaptive αβTh17 cells in acute respiratory distress syndrome. Journal of Immunology 195: 87–95.

    Article  CAS  Google Scholar 

  37. Risso, K., G. Kumar, M. Ticchioni, C. Sanfiorenzo, J. Dellamonica, F. Guillouet-de Salvador, G. Bernardin, C.H. Marquette, and P.M. Roger. 2015. Early infectious acute respiratory distress syndrome is characterized by activation and proliferation of alveolar T-cells. European Journal of Clinical Microbiology & Infectious Diseases 34: 1111–1118.

    Article  CAS  Google Scholar 

  38. Noack, M., and P. Miossec. 2014. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmunity Reviews 13: 668–677.

    Article  CAS  PubMed  Google Scholar 

  39. D’Alessio, F.R., et al. 2009. CD4+ CD25+ Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. The Journal of Clinical Investigation 119: 2898–2913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guha, M., and N. Mackman. 2002. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. The Journal of Biological Chemistry 277: 32124–32132.

    Article  CAS  PubMed  Google Scholar 

  41. Lee, J.P., Y.C. Li, H.Y. Chen, R.H. Lin, S.S. Huang, H.L. Chen, P.C. Kuan, M.F. Liao, C.J. Chen, and Y.H. Kuan. 2010. Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils. Acta Pharmacologica Sinica 31: 831–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lu, Y., J. Zhou, C. Xu, H. Lin, J. Xiao, Z. Wang, and B. Yang. 2008. JAK/STAT and PI3K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apoptosis in cardiomyocytes. Cellular Physiology and Biochemistry 21: 305–314.

    Article  CAS  PubMed  Google Scholar 

  43. Wu, S., J. Xue, Y. Yang, H. Zhu, F. Chen, J. Wang, G. Lou, Y. Liu, Y. Shi, Y. Yu, C. Xia, Y. Hu, and Z. Chen. 2015. Isoliquiritigenin inhibits interferon-γ-inducible genes expression in hepatocytes through down-regulating activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK and PI3K/Akt signaling pathways. Cellular Physiology and Biochemistry 37: 501–514.

    Article  CAS  PubMed  Google Scholar 

  44. Ma, C.S., G.Y.J. Chew, N. Simpson, A. Priyadarshi, M. Wong, B. Grimbacher, D.A. Fulcher, S.G. Tangye, and M.C. Cook. 2008. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. The Journal of Experimental Medicine 205: 1551–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Renner, E.D., S. Rylaarsdam, S. Aňover-Sombke, A.L. Rack, J. Reichenbach, J.C. Carey, Q. Zhu, A.F. Jansson, J. Barboza, L.F. Schimke, M.F. Leppert, M.M. Getz, R.A. Seger, H.R. Hill, B.H. Belohradsky, T.R. Torgerson, and H.D. Ochs. 2008. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T H 17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. Journal of Allergy and Clinical Immunology 122: 181–187.

    Article  CAS  PubMed  Google Scholar 

  46. Yan, C., P.A. Ward, X. Wang, and H. Gao. 2013. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein delta pathway. The FASEB Journal 27: 2967–2976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao, J., H. Yu, Y. Liu, S.A. Gibson, Z. Yan, X. Xu, A. Gaggar, P.K. Li, C. Li, S. Wei, E.N. Benveniste, and H. Qin. 2016. Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 311: L868–L880.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Cheng Guo and Tin Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Hubei Provincial Hospital of Traditional Chinese Medical, Hubei Province Academy of Traditional Chinese Medicine, Luoyu Road 856#, Wuhan, Hubei, China

    Cheng Guo, Tin Wu & Hongfei Zhu

  2. Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Ling Gao

Authors
  1. Cheng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongfei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ling Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongfei Zhu.

Ethics declarations

Experiments were approved by the Institutional Animal Care and Use Committee at Hubei Province Academy of Traditional Chinese Medicine.

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

Guo, C., Wu, T., Zhu, H. et al. Aquaporin 4 Blockade Attenuates Acute Lung Injury Through Inhibition of Th17 Cell Proliferation in Mice. Inflammation 42, 1401–1412 (2019). https://doi.org/10.1007/s10753-019-01002-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01002-4

KEY WORDS

Search

Navigation