The Underlying Mechanisms of Thoracic Radiation Therapy Induced Lung Diseases: Extracellular Adenosine Production by CD73
Introduction: The lungs fall in the irradiation field for several thoracic cancer therapies. Radiation induced lung injury can cause acute radiation pneumonitis in the early phases of treatment and radiation-induced pulmonary fibrosis during later phases. Damage to normal lung tissue plays a large role in dose limitation for patients receiving radiotherapy for chest malignancies. Although radiation induced pulmonary fibrosis is a severe side effect of thoracic irradiation, its pathogenesis remains poorly understood and no causative radio-protective treatment is available.1-5 Ecto-5′-nucleotidase (CD73) and adenosine play critical roles in the process of inflammation and repair as seen in pulmonary fibrosis. CD73 is found on several cell types within the lung. This presentation examines the protective or harmful implications of adenosine and CD73 in radiation-induced lung disease and their potential as therapeutic targets.11,12 Methods: In 2016 Wirsdorfer et al, studied the effects of CD73 and adenosine in radiation induced lung disease. C57BL/6 wild-type and CD73−/− (Nt5e−/−) mice were used in this study. Mice underwent radiation of the thorax over the course of several weeks. Post irradiation wild type mice were treated with either pegylated ADA to breakdown adenosine or anti CD 73 to inhibit CD 73 function. Blood serum, lung tissue and or bronchoalvelor lavage fluid were collected for analysis.11 Results: It was found that in lung tissue after thoracic irradiation there were increased levels of fibrosis, CD73, adenosine and pro fibrotic factors (OPN and TGF- β). There was also an increase in active caspase-3 levels and increased leakage of albumin. Mice deficient of the CD73 gene, had no accumulation of adenosine, or OPN and TGF-β, and had decreased lung fibrosis. Treatment with PEG-ADA reduced the severity of radiation-induced fibrosis by almost 40% (P< 0.01). Treatment with CD73 inhibitors (TY/23) reduced severity of radiation-induced lung fibrosis in all treated mice by more than 25% (P<0.05).11,12 Conclusion: Despite the obvious benefits of CD 73 deficiency after WTI, targeting of CD73 or adenosine did not provide complete protection against radiation induced lung disease. The beneficial effects of adenosine in other models of lung inflammation and fibrosis make it likely that therapeutic inhibition of CD73 may reduce protective effects of CD73-dependent adenosine signaling.6,11,12 Various mechanisms are involved. CD-73 and adenosine signaling also leads to an increase in profibrotic macrophage phenotypes and alveolar macrophage cluster formation.8 Thoracic irradiation also increases Bcl2 mRNA in ACEII cells which is shown to increase cellular senescence.9 Further investigation of other pathways is necessary for prevention and treatment options.
- Bledsoe, Trevor J., et al. “Radiation Pneumonitis.” Clinics in Chest Medicine, vol. 38, no. 2, 2017, pp. 201–208., doi:10.1016/j.ccm.2016.12.004.
- Giridhar, Prashanth, et al. “Radiation Induced Lung Injury: Prediction, Assessment and Management.” Asian Pacific Journal of Cancer Prevention, vol. 16, no. 7, 2015, pp. 2613–2617., doi:10.7314/apjcp.2015.16.7.2613.
- Huang, Yijuan, et al. “The Cellular and Molecular Mechanism of Radiation-Induced Lung Injury.” Medical Science Monitor, vol. 23, 2017, pp. 3446–3450., doi:10.12659/msm.902353.
- Hurmuz, Pervin, et al. “Evaluation of the Effect of Changes in Dose Rate on Rat Lung Cells.” Technology in Cancer Research & Treatment, vol. 14, no. 3, 2014, pp. 343–349., doi:10.1177/1533034614547450.
- Jain, Varsha, and Abigail T. Berman. “Radiation Pneumonitis: Old Problem, New Tricks.” Cancers, vol. 10, no. 7, 2018, p. 222., doi:10.3390/cancers10070222.
- Kaku, H., Cheng, K. F., Al-Abed, Y., & Rothstein, T. L. (2014). A Novel Mechanism of B Cell–Mediated Immune Suppression through CD73 Expression and Adenosine Production. The Journal of Immunology,193(12), 5904-5913. doi:10.4049/jimmunol.1400336
- Klein, D., Schmetter, A., Imsak, R., Wirsdörfer, F., Unger, K., Jastrow, H., . . . Jendrossek, V. (2016). Therapy with Multipotent Mesenchymal Stromal Cells Protects Lungs from Radiation-Induced Injury and Reduces the Risk of Lung Metastasis. Antioxidants & Redox Signaling,24(2), 53-69. doi:10.1089/ars.2014.6183
- Leve, S. D., Wirsdörfer, F., Cappuccini, F., Schütze, A., Meyer, A. V., Röck, K., . . . Jendrossek, V. (2017). Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs. The FASEB Journal,31(7), 2869-2880. doi:10.1096/fj.201601228r
- Pan, J., Li, D., Xu, Y., Zhang, J., Wang, Y., Chen, M., . . . Meng, A. (2017). Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice. International Journal of Radiation Oncology*Biology*Physics,99(2), 353-361. doi:10.1016/j.ijrobp.2017.02.216
- Simone, Charles B. “Thoracic Radiation Normal Tissue Injury.” Seminars in Radiation Oncology, vol. 27, no. 4, 2017, pp. 370–377., doi:10.1016/j.semradonc.2017.04.009.
- Wirsdörfer, F., Leve, S. D., Cappuccini, F., Eldh, T., Meyer, A. V., Gau, E., . . . Jendrossek, V. (2016, May 15). Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis. Retrieved from http://cancerres.aacrjournals.org/content/76/10/3045
- Wirsdörfer, F., & Jendrossek, V. (2017). Modeling DNA damage-induced pneumopathy in mice: Insight from danger signaling cascades. Radiation Oncology,12(1). doi:10.1186/s13014-017-0865-1