, Volume 194, Issue 1, pp 67–74 | Cite as

Delayed Administration of WP1066, an STAT3 Inhibitor, Ameliorates Radiation-Induced Lung Injury in Mice

  • Jiahua YuEmail author
  • Xiaopeng Yuan
  • Yang Liu
  • Kaishuo Zhang
  • Jie Wang
  • Haowen Zhang
  • Fenju LiuEmail author



The present study was designed to investigate the effects of WP1066, a specific inhibitor of STAT3 signaling, on radiation-induced lung injury in mice.


C57BL/6J mice were subjected to a single thoracic irradiation of 15 Gy X-ray and WP1066 was administrated through intraperitoneal injection. The early and delayed treatment groups were treated with WP1066 during the first 2 weeks and the second 2 weeks, respectively. The therapeutic effects of WP1066 were evaluated by survival analysis, histological examination, and measurement of inflammatory parameters and collagen deposition. The activation of STAT3 pathway was also estimated by immunohistochemical staining and Western blotting.


Delayed treatment of WP1066, but not early treatment, prolonged survival time and prevented the development of radiation pneumonitis and the subsequent lung fibrosis in mice. WP1066 treatment also significantly suppressed the activation of STAT3 signaling in the irradiated lung tissues.


The activation of STAT3 pathway might play an important part in the pathogenesis of radiation-induced lung injury. The protective effects of delayed treatment of WP1066 suggested STAT3 signaling could be a therapeutic target for radiation pneumonitis.


WP1066 STAT3 Radiation pneumonitis Inflammation Cytokine 



This work was supported by grants from the National Natural Science Foundation of China (No. 81202149), the University Natural Science Research Project of Jiangsu Province (13KJB310016), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Compliance with Ethical Standards

Conflict of interest



  1. 1.
    Vogelius IR, Bentzen SM (2012) A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol 51(8):975–983. doi: 10.3109/0284186X.2012.718093 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Williams JP, Johnston CJ, Finkelstein JN (2010) Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets 11(11):1386–1394PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Abid SH, Malhotra V, Perry MC (2001) Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol 13(4):242–248CrossRefPubMedGoogle Scholar
  4. 4.
    Kong FM, Ten Haken R, Eisbruch A et al (2005) Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Semin Oncol 32(2 Suppl 3):S42–S54CrossRefPubMedGoogle Scholar
  5. 5.
    Hong JH, Chiang CS, Tsao CY et al (1999) Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int J Radiat Biol 75(11):1421–1427CrossRefPubMedGoogle Scholar
  6. 6.
    Ding NH, Li JJ, Sun LQ (2013) Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets 14(11):1347–1356PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Ghafoori P, Marks LB, Vujaskovic Z et al (2008) Radiation-induced lung injury. Assessment, management, and prevention. Oncology (Williston Park) 22(1):37–47Google Scholar
  8. 8.
    Yu H, Jove R (2004) The STATs of cancer-new molecular targets come of age. Nat Rev Cancer 4(2):97–105. doi: 10.1038/nrc1275 CrossRefPubMedGoogle Scholar
  9. 9.
    Siva S, MacManus M, Kron T et al (2014) A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer. PLoS One 9(10):e109560. doi: 10.1371/journal.pone.0109560 PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Chen Y, Rubin P, Williams J et al (2001) Circulating IL-6 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 49(3):641–648CrossRefPubMedGoogle Scholar
  11. 11.
    Arpin D, Perol D, Blay JY et al (2005) Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis. J Clin Oncol 23(34):8748–8756. doi: 10.1200/JCO.2005.01.7145 CrossRefPubMedGoogle Scholar
  12. 12.
    Chen Y, Hyrien O, Williams J et al (2005) Interleukin (IL)-1A and IL-6: applications to the predictive diagnostic testing of radiation pneumonitis. Int J Radiat Oncol Biol Phys 62(1):260–266. doi: 10.1016/j.ijrobp.2005.01.041 CrossRefPubMedGoogle Scholar
  13. 13.
    Gao H, Ward PA (2007) STAT3 and suppressor of cytokine signaling 3: potential targets in lung inflammatory responses. Expert Opin Ther Targets 11(7):869–880. doi: 10.1517/14728222.11.7.869 CrossRefPubMedGoogle Scholar
  14. 14.
    O’Donoghue RJ, Knight DA, Richards CD et al (2012) Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Mol Med 4(9):939–951. doi: 10.1002/emmm.201100604 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Prele CM, Yao E, O’Donoghue RJ et al (2012) STAT3: a central mediator of pulmonary fibrosis? Proc Am Thorac Soc 9(3):177–182. doi: 10.1513/pats.201201-007AW CrossRefPubMedGoogle Scholar
  16. 16.
    Ma X, Chen R, Liu X et al (2013) Effects of matrine on JAK-STAT signaling transduction pathways in bleomycin-induced pulmonary fibrosis. Afr J Tradit Complement Altern Med 10(3):442–448PubMedCentralPubMedGoogle Scholar
  17. 17.
    Kong LY, Abou-Ghazal MK, Wei J et al (2008) A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clin Cancer Res 14(18):5759–5768. doi: 10.1158/1078-0432.CCR-08-0377 PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Rube CE, Wilfert F, Palm J et al (2004) Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. Strahlenther Onkol 180(7):442–448. doi: 10.1007/s00066-004-1265-7 CrossRefPubMedGoogle Scholar
  19. 19.
    Hong ZY, Song KH, Yoon JH et al (2015) An experimental model-based exploration of cytokines in ablative radiation-induced lung injury in vivo and in vitro. Lung 193(3):409–419. doi: 10.1007/s00408-015-9705-y CrossRefPubMedGoogle Scholar
  20. 20.
    Hussain SF, Kong LY, Jordan J et al (2007) A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res 67(20):9630–9636. doi: 10.1158/0008-5472.CAN-07-1243 CrossRefPubMedGoogle Scholar
  21. 21.
    Verstovsek S, Manshouri T, Quintas-Cardama A et al (2008) WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Clin Cancer Res 14(3):788–796. doi: 10.1158/1078-0432.CCR-07-0524 CrossRefPubMedGoogle Scholar
  22. 22.
    Judd LM, Menheniott TR, Ling H et al (2014) Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS One 9(5):e95993. doi: 10.1371/journal.pone.0095993 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Zhou X, Ren Y, Liu A et al (2014) WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis. Sci Rep 4:7461. doi: 10.1038/srep07461 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    You S, Li R, Park D et al (2014) Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer. Mol Cancer Ther 13(3):606–616. doi: 10.1158/1535-7163.MCT-13-0608 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Zhang Q, Zhang C, He J et al (2015) STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma. Tumour Biol 36(3):2135–2142. doi: 10.1007/s13277-014-2823-y CrossRefPubMedGoogle Scholar
  26. 26.
    Rube CE, Uthe D, Wilfert F et al (2005) The bronchiolar epithelium as a prominent source of pro-inflammatory cytokines after lung irradiation. Int J Radiat Oncol Biol Phys 61(5):1482–1492. doi: 10.1016/j.ijrobp.2004.12.072 CrossRefPubMedGoogle Scholar
  27. 27.
    Saito-Fujita T, Iwakawa M, Nakamura E et al (2011) Attenuated lung fibrosis in interleukin 6 knock-out mice after C-ion irradiation to lung. J Radiat Res 52(3):270–277CrossRefPubMedGoogle Scholar
  28. 28.
    Ogata T, Yamazaki H, Teshima T et al (2010) Early administration of IL-6RA does not prevent radiation-induced lung injury in mice. Radiat Oncol 5:26. doi: 10.1186/1748-717X-5-26 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Liu G, Friggeri A, Yang Y et al (2010) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 207(8):1589–1597. doi: 10.1084/jem.20100035 PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Case SR, Martin RJ, Jiang D et al (2011) MicroRNA-21 inhibits toll-like receptor 2 agonist-induced lung inflammation in mice. Exp Lung Res 37(8):500–508. doi: 10.3109/01902148.2011.596895 CrossRefPubMedGoogle Scholar
  31. 31.
    Hutchins AP, Diez D, Miranda-Saavedra D (2013) The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genom 12(6):489–498. doi: 10.1093/bfgp/elt028 CrossRefGoogle Scholar
  32. 32.
    Yu H, Lee H, Herrmann A et al (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746. doi: 10.1038/nrc3818 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences (RAD-X)Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhouPeople’s Republic of China

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