Radiation Oncology Journal

  • 제23권3호
  • /
  • Pages.161-168
  • /
  • 2005
  • /
  • 2234-1900(pISSN)
  • /
  • 2234-3156(eISSN)
대한방사선종양학회 (The Korean Society for Radiation Oncology)
권호 표지

방사선조사된 폐에서 Melatonin에 의한 TGF-${\beta}1$ 발현의 변화

The Change of Transforming Growth Factor ${\beta}1(TGF-{\beta}1)$ Expression by Melatonin in Irradiated Lung

  • 장성순 (가톨릭대학교 의과대학 방사선종양학교실) ;
  • 최일봉 (가톨릭대학교 의과대학 방사선종양학교실)
  • Jang, Seong-Soon (Department of Radiation Oncology, College on Medicine, The Catholic University of Korea) ;
  • Choi, Ihl-Bohng (Department of Radiation Oncology, College on Medicine, The Catholic University of Korea)
  • 발행 : 2005.09.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

목적: 강력한 항산화 효과를 지닌 melatonin을 전처치하였을 때 방사선유도성 섬유증 과정에서 중요한 사이토카인인 $TGF-{\beta}1$의 변화된 발현양상을 마우스 폐에서 연구하였다. 대상 및 방법: C57BL/6 마우스를 실험군에 따라 세 군(대조군, 방사선조사 단독군, melatonin 전처치군(방사선조사 1시간 전에 300 mg/kg 복강주사))으로 분류하고 양측 흉곽에 12 Gy의 선량을 단일조사하였다. 방사선조사 후 2주와 4주의 폐조직에서 $TGF-{\beta}1$ mRNA 발현수준을 측정하기 위해 semiquantitive RT-PCR를 시행하였고, $TGF-{\beta}1$ protein 발현의 수준과 위치를 보기 위해 면역조직화학염색을 시행하였다. 결과: 2주 후에 측정된 mRNA 발현은 방사선조사 단독군과 melatonin 전처치군에서 각각 대조군의 1.92배와 1.80배 증가된 수준을 보였고(p=0.064), 4주 후에는 각각 2.38배와 1.94배 수준의 증가된 발현을 보였다(p=0.004). $TGF-{\beta}1$ protein의 발현은 조직병리학적으로 방사선손상 영역에서 주로 관찰되었는데 폐포 대식세포와 폐포벽의 상피세포들이 주요 근원이었다. 발현수준은 2주완 4주 후에 각각 $15.8\%\;vs\;16.9\%$ (P=0.565), 그리고 $36.1\%\;vs\;25.7\%$ (p=0.009)이었다. 결론: Melatonin 전처치로 방사선조사에 의한 $TGF-{\beta}1$ mRNA와 protein의 발현이 4주 후에 유의하게 감소됨을 관찰하였다. 따라서 방사선으로 인한 폐손상 시에 항섬유증 약물로의 사용가능성을 확인하였다.

Purpose: The changed expressions of $TGF-{\beta}1$, as a key cytokine in the fibrotic process, due to melatonin with potent antioxidative effects, were investigated in the irradiated lung using fibrosis-sensitive C57BL/6 mice. Materials and Methods: Female C57BL/6 mice were divided into control irradiation-only, and melatonin (300 mg/kg i.p. 1 hr before irradiation) pretreatment groups. The thoraces of the mice were irradiated with a single dose of 12 Gy. The mRNA expressions of $TGF-{\beta}1$ in the lung tissue 2 and 4 weeks after irradiation were quantified using semiquantitive RT-PCR, and the cellular origin and expression levels of $TGF-{\beta}1$ protein were identified using immunohistochemical staining. Results: The relative mRNA expression levels in the irradiation-only and melatonin pretreatment groups 2 and 4 weeks after irradiation were 1.92- and 1.80-fold (p=0.064) and 2.38- and 1.94-fold (p=0.004) Increased, respectively compared to those in the control group. increased expressions of $TGF-{\beta}1$ protein were prominently detected in regions of histopathologicai radiation injury, with alveolar macrophages and septal epithelial cells serving as important sources of $TGF-{\beta}1$ expression. At 2 and 4 weeks after irradiation, the expression levels of protein were $15.8\%\;vs.\;16.9\%$ (p=0.565) and $36.1\%\;vs.\;25.7\%$ (p=0.009), respectively. Conclusion: The mRNA and protein expressions of $TGF-{\beta}1$ in the lung tissue following thoracic irradiation with 12 Gy were significantly decreased by melatonin pretreatment at 4 weeks. These results indicate that melatonin may have a possible application as an antifibrotic agent in radiation-induced lung injury.

키워드

참고문헌

  1. Poli G, Parola M. Oxidative damage and fibrogenesis. Free Radic Biol Med 1997;22:287-305 https://doi.org/10.1016/S0891-5849(96)00327-9
  2. Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 1995;33:99-109 https://doi.org/10.1016/0360-3016(95)00095-G
  3. Rodemann HP, Bamberg M. Cellular basis of radiation-induced fibrosis. Radiother Oncol 1995;35:83-90 https://doi.org/10.1016/0167-8140(95)01540-W
  4. Martin M, Lefaix JL, Delanian S. TGF-$\beta$1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 2000;47:277-290 https://doi.org/10.1016/S0360-3016(00)00435-1
  5. Mehta V. Radiation pneuminitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys 2005;article in press https://doi.org/10.1016/j.ijrobp.2005.03.047
  6. Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med 2000;225:9-22 https://doi.org/10.1046/j.1525-1373.2000.22502.x
  7. Border WA, Noble NA. Transforming growth factor $\beta$ in tissue fibrosis. N Engl J Med 1994;331:1286-1292 https://doi.org/10.1056/NEJM199411103311907
  8. Hill RP, Rodemann HP, Hendry JH, Roberts SA, Anscher MS. Normal tissue radiobiology: from the laboratory to the clinic. Int J Radiat Oncol Biol Phys 2001;49:353-365 https://doi.org/10.1016/S0360-3016(00)01484-X
  9. Anscher MS, Kong FM, Andrews K, et al. Plasma transforming growth factor $\beta$1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 1998;41:1029-1035 https://doi.org/10.1016/S0360-3016(98)00154-0
  10. Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-$\beta$ signaling in regulation of cell growth and differentiation. Immunol Lett 2002;82:85-91 https://doi.org/10.1016/S0165-2478(02)00023-8
  11. Yi ES, Bedoya A, Lee H, et al. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation 1996;20:339-352 https://doi.org/10.1007/BF01486737
  12. Johnston CJ, Piedboeuf B, Baggs R, Rubin P, Finkelstein JN. Differences in correlation of mRNA gene expression in mice sensitive and resistant to radiation-induced pulmonary fibrosis. Radiat Res 1995;142:197-203 https://doi.org/10.2307/3579029
  13. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor $\beta$ (TGF-$\beta$) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int J Radiat Oncol Biol Phys 2000;47:1033-1042 https://doi.org/10.1016/S0360-3016(00)00482-X
  14. Brzezinski A. Mechanisms of disease: melatonin in humans. N Engl J Med 1997;336:186-195 https://doi.org/10.1056/NEJM199701163360306
  15. Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys 2004;59:639-653 https://doi.org/10.1016/j.ijrobp.2004.02.006
  16. Vijayalaxmi, Thomas CR, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002;20:2575-2601 https://doi.org/10.1200/JCO.2002.11.004
  17. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996;53:43-46 https://doi.org/10.1159/000227533
  18. Tahan V, Ozaras R, Canbakan B, et al. Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats. J Pineal Res 2004;37:78-84 https://doi.org/10.1111/j.1600-079X.2004.00137.x
  19. Arslan SO, Zerin M, Vural H, Coskun A. The effect of melatonin on bleomycin-induced pulmonary fibrosis in rats. J Pineal Res 2002;32:21-25 https://doi.org/10.1034/j.1600-079x.2002.10796.x
  20. Drobnik J, Dabrowski R. Pinealectomy-induced elevation of collagen content in the intact skin is suppressed by melatonin application. Cytobios 1999;100:49-55€
  21. Drobnik J, Dabrowski R. Melatonin suppresses the pinealectomy- induced elevation of collagen content in a wound. Cytobios 1996;85:51-58