Abstract
Radiation-induced lung injury (RILI) is a common complication in cancer patients receiving local thoracic radiation and bone marrow transplantation conditioning. It is divided into early-stage radiation pneumonitis and advanced radiation fibrosis of the lung. This severely hampers the quality of life and survival of cancer patients. Meanwhile, RILI is a major factor limiting radiation doses in clinical practice, which affects the local control of cancer. Unfortunately, the mechanism of RILI is still not well defined, and there are no treatment options available for these patients. In this review we summarize the methods and agents used for the treatment and prevention of RILI, with the aim of increasing understanding of RILI.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Voxel-by-voxel correlation between radiologically radiation induced lung injury and dose after image-guided, intensity modulated radiotherapy for lung tumors. Physica Medica 42, 150–156 (2017).
- 2. . Computed tomography appearance of early radiation injury to the lung: correlation with clinical and dosimetric factors. Int. J. Radiat. Oncol. Biol. Phys. 81(1), 97–103 (2011).
- 3. . Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes. Eur. J. Radiol. 79(1), 147–154 (2011).
- 4. PO-0679: radiation-induced lung injury (RILI): correlation with dosimetric parameters and pulmonary function. Radiat. Oncol. 106, S261 (2013).
- 5. . Management and outcome of symptomatic radiation induced lung injury in non-small cell lung cancer. Chin. J. Radiat. Oncol. 22(3), 201–204 (2013).
- 6. Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients. Radiother. Oncol. 80(1), 93–97 (2006).
- 7. . Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice. J. Radiat. Res. 57(5), 505–511 (2016).
- 8. Inhalative steroids as an individual treatment in symptomatic lung cancer patients with radiation pneumonitis grade II after radiotherapy – a single-centre experience. Radiat. Oncol. 11, 12 (2016).
- 9. A PPAR-gamma agonist attenuates pulmonary injury induced by irradiation in a murine model. Lung Cancer 90(3), 405–409 (2015).
- 10. Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Am. J. Physiol. Lung Cell Mol. Physiol. 301(1), L125–L134 (2011). • The treatment agents were safe. Animal study indicated that the drugs contributed to the TGF-β signaling inhibition and development of alveolus.
- 11. . Organ fibrosis inhibited by blocking transforming growth factor-beta signaling via peroxisome proliferator-activated receptor gamma agonists. HBPD Int. 11(5), 467–478 (2012).
- 12. PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 288(6), L1146–L1153 (2005).
- 13. . The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. JIM 56(2), 534–538 (2008).
- 14. Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. Am. J. Resp. Cell. Mol. 41(6), 722–730 (2009).
- 15. All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling. Biochem. Biophys. Res. Commun. 491(3), 721–726 (2017).
- 16. All-trans-retinoic acid prevents radiation- or bleomycin-induced pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 174(12), 1352–1360 (2006).
- 17. The role of all-trans retinoic acid in bleomycin-induced pulmonary fibrosis in mice. Exp. Lung Res. 38(2), 82–89 (2012).
- 18. All-trans retinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-beta1/Smad3 signaling pathway in rats. Lab. Invest. 93(11), 1219–1231 (2013).
- 19. All-trans-retinoic acid (ATRA) is of no benefit in bleomycin-induced lung injury. Pulm. Pharmacol. Ther. 14(5), 403–407 (2001).
- 20. Effect of pretreatment with high-dose ulinastatin in preventing radiation-induced pulmonary injury in rats. Eur. J. Pharmacol. 603(1-3), 114–119 (2009).
- 21. . Ulinastatin protects rats from sepsis-induced acute lung injury by suppressing the JAK-STAT3 pathway. J. Cell. Biochem.
doi: 10.1002/jcb.27550 (.2018) (Epub ahead of print). - 22. Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGFbeta1, TNFalpha and NFkappaB. Mol. Med. Rep. 17(1), 1717–1723 (2018).
- 23. Ulinastatin attenuates lung ischemia-reperfusion injury in rats by inhibiting tumor necrosis factor alpha. Transplant. Proc. 38(9), 2777–2779 (2006).
- 24. . Mitigation of radiation induced pulmonary vascular injury by delayed treatment with captopril. Respirology 17(8), 1261–1268 (2012).
- 25. . Radiation damage to the lung: mitigation by angiotensin-converting enzyme (ACE) inhibitors. Respirology 17(1), 66–71 (2012). •• ACEI is the first and most effective alleviator. ACE is rich in the lung tissues. These bring hope for the attenuation of RILI.
- 26. . Decreased risk of radiation pneumonitis with incidental concurrent use of angiotensin-converting enzyme inhibitors and thoracic radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 84(1), 238–243 (2012).
- 27. Effect of an angiotensin II receptor blocker and two angiotensin converting enzyme inhibitors on transforming growth factor-beta (TGF-beta) and alpha-actomyosin (alpha SMA), important mediators of radiation-induced pneumopathy and lung fibrosis. Curr. Pharm. Des. 13(13), 1307–1316 (2007).
- 28. . Renin-angiotensin system inhibitors might help to reduce the development of symptomatic radiation pneumonitis after stereotactic body radiotherapy for lung cancer. Clin. Lung Cancer 17(3), 189–197 (2016).
- 29. Do angiotensin-converting enzyme inhibitors reduce the risk of symptomatic radiation pneumonitis in patients with non-small cell lung cancer after definitive radiation therapy? Analysis of a single-institution database. Int. J. Radiat. Oncol. Biol. Phys. 87(5), 1071–1077 (2013).
- 30. . Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm. Med. 17(1), 94 (2017).
- 31. . Azithromycin ameliorates airway remodeling via inhibiting airway epithelium apoptosis. Life Sci. 170, 1–8 (2017).
- 32. . Efficacy of azithromycin for treatment of acute exacerbation of chronic fibrosing interstitial pneumonia: a prospective, open-label study with historical controls. Respiration 87(6), 478–484 (2014).
- 33. Regional differences in susceptibiity of bronchial epithelium to mesenchymal transition and inhibition by the macrolide antibiotic azithromycin. PloS ONE 7(12), e52309 (2012).
- 34. Azithromycin attenuates acute radiation-induced lung injury in mice. Oncol. Lett. 14(5), 5211–5220 (2017). •• Azithromycin could attenuate RILI through anti-inflammatory and antifibrotic effects, with satisfactory safety.
- 35. Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer. Eur. J. Cancer 44(16), 2425–2432 (2008).
- 36. Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis. 33(1), 130–148 (2019).
- 37. . Effects of berberine on acute necrotizing pancreatitis and associated lung injury. Pancreas 46(8), 1046–1055 (2017).
- 38. . Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappaB dependant TGF-beta activation: a biphasic experimental study. Toxicol. Lett. 219(2), 178–193 (2013).
- 39. Cavidine ameliorates lipopolysaccharide-induced acute lung injury via NF-kappaB signaling pathway in vivo and in vitro. Inflammation 40(4), 1111–1122 (2017).
- 40. Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-kappaB signaling pathways. Biomed. Pharmacother. 82, 489–497 (2016).
- 41. COX-2 inhibition attenuates lung injury induced by skeletal muscle ischemia reperfusion in rats. Int. Immunopharmacol. 31, 116–122 (2016).
- 42. . Celecoxib and radiation therapy in non-small-cell lung cancer. Oncology (Williston Park, N.Y.) 18(Suppl. 14), 10–14 (2004).
- 43. . Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP. Am. J. Transl. Res. 9(3), 1088–1100 (2017).
- 44. Radiosensitivity enhancement by celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, via COX-2-dependent cell cycle regulation on human cancer cells expressing differential COX-2 levels. Cancer Res. 65(20), 9501–9509 (2005). •• Celecoxib showed synergistic effects on radiation, and it also contributed to the repair of RILI.
- 45. . Antitumor enhancement of celecoxib, a selective cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing cyclooxygenase-2. J. Exp. Clin. Cancer Res. CR 27, 66 (2008).
- 46. . Mitigation and treatment of radiation-induced thoracic injury with a cyclooxygenase-2 inhibitor, celecoxib. Int. J. Radiat. Oncol. Biol. Phys. 85(2), 472–476 (2013).
- 47. . Protective role of cyclooxygenase (COX)-2 in experimental lung injury: evidence of a lipoxin A4-mediated effect. J. Surg. Res. 175(1), 176–184 (2012).
- 48. . Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J. Immunol. Res. 174(8), 5033–5039 (2005).
- 49. Amelioration of radiation-induced lung injury by halofuginone: an experimental study in Wistar-Albino rats. Hum. Exp. Toxicol. 36(6), 638–647 (2017).
- 50. . The role of halofuginone in fibrosis: more to be explored? J. Leukoc. Biol. 102(6), 1333–1345 (2017).
- 51. . The effect of halofuginone in the amelioration of radiation induced-lung fibrosis. Med. Hypotheses 80(4), 357–359 (2013). •• Halofuginone showed protective effects against radiation-induced soft tissue fibrosis. Its antifibrotic mechanism is suitable for the radiation fibrosis of lung, which may be effective for treating pulmonary fibrosis.
- 52. Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone. J. Biol. Chem. 279(15), 15167–15176 (2004).
- 53. . Halofuginone: a novel antifibrotic therapy. Gen. Pharmacol. 30(4), 445–450 (1998).
- 54. . Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract. World J. Gastroenterol. 20(40), 14778–14786 (2014).
- 55. . Halofuginone does not reduce fibrosis in bleomycin-induced lung injury. Life Sci. 71(14), 1599–1606 (2002).
- 56. Genetic variants in the plasminogen activator inhibitor-1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients. Cancer Med. 6(3), 681–688 (2017).
- 57. Conditional Plasminogen Activator Inhibitor Type 1 deletion in the endothelial compartment has no beneficial effect on radiation-induced whole-lung damage in mice. Int. J. Radiat. Oncol. Biol. Phys. 99(4), 972–982 (2017).
- 58. Truncated Plasminogen Activator Inhibitor-1 protein protects from pulmonary fibrosis mediated by irradiation in a murine model. Int. J. Radiat. Oncol. Biol. Phys. 94(5), 1163–1172 (2016).
- 59. Effect of liposomemediated HSP27 transfection on collagen synthesis in alveolar type II epithelial cells. Mol. Med. Rep. 17(5), 7319–7324 (2018).
- 60. Therapeutic effects of bone marrow-derived mesenchymal stem cells on radiation-induced lung injury. Oncol. Rep. 35(2), 731–738 (2016).
- 61. Therapeutic effects of human umbilical cord-derived mesenchymal stem cells on canine radiation-induced lung injury. Int. J. Radiat. Oncol. Biol. Phys. 102(2), 407–416 (2018).
- 62. Therapy with multipotent mesenchymal stromal cells protects lungs from radiation-induced injury and reduces the risk of lung metastasis. Antioxid. Redox. Signal. 24(2), 53–69 (2016). •• Theauthors proposed a new concept that radiation-induced injury of pulmonary vessels contributed to the pulmonary metastasis. Mesenchymal stem cells could inhibit the metastasis by attenuating the vascular injury.
- 63. . Interaction between mesenchymal stem cells and endothelial cells restores endothelial permeability via paracrine hepatocyte growth factor in vitro. Stem. Cell Res. Ther. 6, 44 (2015).
- 64. . Hepatocyte growth factor is required for mesenchymal stromal cell protection against bleomycin-induced pulmonary fibrosis. Stem Cells Transl. Med. 5(10), 1307–1318 (2016).
- 65. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am. J. Physiol. Lung C 303(11), L967–977 (2012).
- 66. . Bone marrow-derived mesenchymal stem cells enhance autophagy via PI3K/AKT signalling to reduce the severity of ischaemia/reperfusion-induced lung injury. J. Cell. Mol. Med. 19(10), 2341–2351 (2015).
- 67. . Mesenchymal stem cells – a new hope for radiotherapy-induced tissue damage? Cancer Lett. 366(2), 133–140 (2015).
- 68. Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-beta type II receptor gene. Cancer Gene Ther. 13(9), 864–872 (2006).
- 69. . Antitransforming growth factor-beta antibody 1D11 ameliorates normal tissue damage caused by high-dose radiation. Int. J. Radiat. Oncol. Biol. Phys. 65(3), 876–881 (2006).
- 70. . Adenovirus-mediated FOXP3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice. Gene Ther. 24(2), 104–112 (2017). •• FOXP3 overexpression inhibited the recruitment of the inflammatory cells and the deposit of collagen, which brings hope for treating RILI by gene therapy.
- 71. Hypo-CpG methylation controls PTEN expression and cell apoptosis in irradiated lung. Free Radic. Res. 50(8), 875–886 (2016).
- 72. . Oxidative stress mediates radiation lung injury by inducing apoptosis. Int. J. Radiat. Oncol. Biol. Phys. 83(2), 740–748 (2012).
- 73. . Antioxidant and anti-genotoxic properties of cerium oxide nanoparticles in a pulmonary-like cell system. Arch. Toxicol. 90(2), 269–278 (2016).
- 74. Silicon dioxide nanoparticles enhance endotoxin-induced lung injury in mice. Molecules 23 (.9), 2247 (2018).
- 75. Anti-inflammatory and antioxidant effect of cerium dioxide nanoparticles immobilized on the surface of silica nanoparticles in rat experimental pneumonia. Biomed. Pharmacother. 92, 69–77 (2017).
- 76. Cerium oxide nanoparticles protect lung from radiation-induced injury in CBA/J mice. Int. J. Radiat. Oncol. Biol. Phys. 84(3), S683–S683 (2012).
- 77. Cerium oxide nanoparticles: a potential medical countermeasure to mitigate radiation-induced lung injury in CBA/J mice. Radiat. Res. 185(5), 516–526 (2016). •• CNPs showed surface regenerative capacity and could effectively control the active oxygen and nitrogen. CNPs showed protective effects against the RILI by lethal dose. It may serve as a novel option for treating RILI.