Skip to main content

Advertisement

SpringerLink
Log in

Blockade of Aquaporin 4 Inhibits Irradiation-Induced Pulmonary Inflammation and Modulates Macrophage Polarization in Mice

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

Abstract

To investigate the effects of aquaporin 4 (AQP4) inhibitor in irradiation-induced pulmonary inflammation in mice. A single dose of 75 Gy was delivered to the left lung of mice to induce radiation pneumonitis. For inhibition of AQP4, 200 mg/kg of TGN-020 was administered i.p. one time per 2 days post-irradiation. Blockade of AQP4 with TGN-020 resulted in the inhibition of inflammatory cell infiltration and the downregulation of inflammatory cytokines (IL-6, IL-17, and TGF-β), chemokines (MIP1a and MCP1), fibrosis-related (Col3al and Fn1), and M2 macrophage marker (Arg1) post-irradiation. Immunofluorescence staining indicated that there was significant fewer M2 macrophage infiltration in the irradiated lung tissues from mice treated with TGN-020. Additionally, depletion of macrophages with liposome clodronate resulted in alleviated lung injury induced by irradiation. Furthermore, adoptive transfer of M1 or M2 macrophages into clodronate-treated mice was performed. The results showed that the administration of M2 macrophages fully reversed the clodronate-induced beneficial effect on inflammation score, thickness, and fibrosis. However, transfer of M1 macrophages only impacted the inflammation score and thickness and did not affect lung fibrosis. AQP4 blockade alleviated the development and severity of irradiated lung damage. This was associated with attenuated infiltration of inflammatory cell, decreased production of pro-inflammatory cytokines, and inhibited activation of M2 macrophages.

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

Similar content being viewed by others

References

  1. Lancet, T. 2013. Lung cancer: A global scourge. Lancet 382: 659.

    Article  Google Scholar 

  2. Onishi, H., and T. Araki. 2013. Stereotactic body radiation therapy for stage I non-small-cell lung cancer: A historical overview of clinical studies. Japanese Journal of Clinical Oncology 43: 345–350.

    Article  Google Scholar 

  3. Simone, C.B., 2nd, B. Wildt, A.R. Haas, G. Pope, R. Rengan, and S.M. Hahn. 2013. Stereotactic body radiation therapy for lung cancer. Chest 143: 1784–1790.

    Article  CAS  Google Scholar 

  4. Ehta, V.I.M. 2005. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention. International Journal of Radiation Oncology, Biology, Physics 63: 5–24.

    Article  Google Scholar 

  5. Yarnold, J., and M.C. Vozenin Brotons. 2010. Pathogenetic mechanisms in radiation fibrosis. Radiother. Oncol. 97: 149–161.

    Article  CAS  Google Scholar 

  6. Atsuya, T., T. Yuichiro, and S. Naoko. 2018. Clarithromycin mitigates radiation pneumonitis in patients with lung cancer treated with stereotactic body radiotherapy. J Thorac Dis. 10 (1): 247–261.

    Article  Google Scholar 

  7. Tsoutsou, P.G., and M.I. Koukourakis. 2006. Radiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future research. International Journal of Radiation Oncology, Biology, Physics 66: 1281–1293.

    Article  Google Scholar 

  8. Schaue, D., and W.H. McBride. 2010. Links between innate immunity and normal tissue radiobiology. Radiation Research 173: 406–417.

    Article  CAS  Google Scholar 

  9. Marks, L.B., X. Yu, Z. Vujaskovic, W. Small Jr., R. Folz, and M.S. Anscher. 2003. Radiation-induced lung injury. Seminars in Radiation Oncology 13: 333–345.

    Article  Google Scholar 

  10. Demaria, S., E. Pikarsky, M. Karin, L.M. Coussens, Y.C. Chen, E.M. El-Omar, G. Trinchieri, S.M. Dubinett, J.T. Mao, E. Szabo, et al. 2010. Cancer and inflammation: Promise for biologic therapy. Journal of Immunotherapy 33: 335–351.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Verkman, A.S. 2013. Biology of AQP4 and anti-AQP4 antibody: Therapeutic implications. Brain Pathol 23 (6): 684–695.

    Article  CAS  Google Scholar 

  13. Sun, C.Y., Y.X. Zhao, and W. Zhong. 2014. The expression of aquaporins 1 and 5 in rat lung after thoracic irradiation. Journal of Radiation Research 55 (4): 683–689.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  15. Xu, M., W. Su, and Q.P. Xu. 2010. Aquaporin-4 and traumatic brain edema. Chinese Journal of Traumatology 13 (2): 103–110.

    CAS  PubMed  Google Scholar 

  16. Liu, S., J. Mao, T. Wang, and X. Fu. 2017. Downregulation of aquaporin-4 protects brain against hypoxia ischemia via anti-inflammatory mechanism. Molecular Neurobiology 54 (8): 6426–6435.

    Article  CAS  Google Scholar 

  17. 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 

  18. Kim, M.-G., S.C. Kim, Y.S. Ko, H.Y. Lee, S.-K. Jo, and W. Cho. 2015. The role of M2 macrophages in the progression of chronic kidney disease following acute kidney injury. PLoS One 10 (12): e0143961.

    Article  Google Scholar 

  19. Li, Q., G. Eades, Y. Yao, Y. Zang, and Q. Zhou. 2014. Characterization of a stem-like subpopulation in basal-like ductal carcinoma in situ (DCIS) lessons. The Journal of Biological Chemistry 289 (3): 1303–1312.

    Article  CAS  Google Scholar 

  20. McCloy, R.A., S. Rogers, C.E. Caldon, T. Lorca, A. Castro, and A. Burgess. 2014. Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 13 (9): 1400–1412.

    Article  CAS  Google Scholar 

  21. Kim, J.Y., D. Shin, Lee Gihyun, J.M. Kim, and D.W. Kim. 2017. Standardized herbal formula PM014 inhibits radiation-induced pulmonary inflammation in mice. Sci Rep 7: 45001.

    Article  CAS  Google Scholar 

  22. Hong, Z.Y., S.H. Eun, K. Park, W.H. Choi, J.I. Lee, E.J. Lee, J.M. Lee, M.D. Story, and J. Cho. 2014. Development of a small animal model to simulate clinical stereotactic body radiotherapy-induced central and peripheral lung injuries. Journal of Radiation Research 55: 648–657.

    Article  CAS  Google Scholar 

  23. Dabjan, M.B., C.M. Buck, and I.L. Jackson. 2016. A survey of changing trends in modelling radiation lung injury in mice: Bringing out the good, the bad, and the uncertain. Laboratory Investigation 96 (9): 936–949.

    Article  Google Scholar 

  24. Alnajar, A., C. Nordhoff, T. Schied, R. Chiquet-Ehrismann, K. Loser, T. Vogl, S. Ludwig, and V. Wixler. 2013. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis. PLoS One 8 (11): e81356.

    Article  Google Scholar 

  25. Kakugawa, T., et al. 2004. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. The European Respiratory Journal 1: 57–65.

    Article  Google Scholar 

  26. Sempowski, G.D., M.P. Beckmann, S. Derdak, and R.P. Phipps. 1994. Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J. Immunol. 152: 3606–3614.

    CAS  PubMed  Google Scholar 

  27. Wu, Z., et al. 2013. Effects of carbon ion beam irradiation on lung injury and pulmonary fibrosis in mice. Experimental and Therapeutic Medicine 5: 771–776.

    Article  Google Scholar 

  28. Wolf, J., S. Rose-John, and C. Garbers. 2014. Interleukin-6 and its receptors: A highly regulated and dynamic system. Cytokine 70: 11–20.

    Article  CAS  Google Scholar 

  29. Scheller, J., A. Chalaris, D. Schmidt-Arras, and S. Rose-John. 2011. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta 1813 (5): 878–888.

    Article  CAS  Google Scholar 

  30. Chen, Y., J. Williams, I. Ding, E. Hernady, W. Liu, T. Smudzin, et al. 2002. Radiation pneumonitis and early circulatory cytokine markers. Seminars in Radiation Oncology 12 (1 Suppl 1): 22–33.

    Google Scholar 

  31. Kolls, J.K., and A. Linden. 2004. Interleukin-17 family members and inflammation. Immunity 21 (4): 467–476.

    Article  CAS  Google Scholar 

  32. Wilson, M.S., S.K. Madala, T.R. Ramalingamet, B.R. Gochuico, I.O. Rosas, A.W. Cheever, et al. 2010. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent. The Journal of Experimental Medicine 207: 535–552.

    Article  CAS  Google Scholar 

  33. Fosslien, E. 2008. Cancer morphogenesis: Role of mitochondrial failure. Annals of Clinical and Laboratory Science 38 (4): 307–329.

    CAS  PubMed  Google Scholar 

  34. Zhang, X.J., J.G. Sun, J. Sun, H. Ming, X.X. Wang, L. Wu, and Z.T. Chen. 2012. Prediction of radiation pneumonitis in lung cancer patients: A systematic review. Journal of Cancer Research and Clinical Oncology 138 (12): 2103–2116.

    Article  Google Scholar 

  35. Johnston, C.J., J.P. Williams, P. Okunieff, and J.N. Finkelstein. 2002. Radiation-induced pulmonary fibrosis: Examination of chemokine and chemokine receptor families. Radiation Research 157: 256–265.

    Article  CAS  Google Scholar 

  36. Wermuth, P.J., and S.A. Jimenez. 2015. The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases. Clinical and Translational Medicine 4: 2.

    Article  Google Scholar 

  37. Mosmann, T.R., H. Cherwinski, M.W. Bond, M.A. Giedlin, and R.L. Coffman. 2005. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. 1986. Journal of Immunology 175: 5–14.

    CAS  Google Scholar 

Download references

Funding

This work was supported by the Health and Family Planning Commission of Hubei Province of China (WJ2015CA002) and Scientific Research Project of Wuhan Health and Family Planning Commission (WX15D65).

Author information

Authors and Affiliations

  1. Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yuhui Li, Hongda Lu, Xiaojuan Lv & Qiu Tang

  2. HLA Typing Laboratory, Blood Center of Wuhan, Wuhan, China

    Wangxia Li

  3. Department of Anesthesiology, Hubei Provincial Hospital of Traditional Chinese Medical, Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China

    Hongfei Zhu

  4. Department of Cardiaovascular Medicine, Wuhan Women and Children Medical Care Center, Tongji Medical College, Huazhong University of Science and Technology, Xianggang Road 16#, Jianghan District, Wuhan, 430000, Hubei, China

    Yuan Long

Authors
  1. Yuhui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongda Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaojuan Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wangxia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongfei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuan Long
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuan Long.

Ethics declarations

The data and maternal were available to the corresponding author.

Conflict of Interests

The authors declare that there is no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Lu, H., Lv, X. et al. Blockade of Aquaporin 4 Inhibits Irradiation-Induced Pulmonary Inflammation and Modulates Macrophage Polarization in Mice. Inflammation 41, 2196–2205 (2018). https://doi.org/10.1007/s10753-018-0862-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-018-0862-z

KEY WORDS

Search

Navigation