ブレオマイシン肺臓炎における細気管支及び肺胞上皮細胞のDNA傷害
ブレオマイシンの細胞傷害を起こす機序は, DNA鎖の切断であると考えられている. そこでマウスのブレオマイシン肺臓炎を対象として, DNA断端の3'-OH基を組織上で特異的に検出可能な in situ biotin-dUTP end-labeling 法を用いてDNA傷害の局在と線維化との関連性を検討した. その結果, ブレオマイシン投与約1時間から12時間後は, 細気管支上皮細胞を中心にDNA傷害がみられ, その後回復するが, 徐々に線維化が進行すると共に肺胞上皮細胞のDNA傷害が増強し遷延していた. 投与直後のDNA傷害はステロイド投与によって影響を受けなかったが, 遷延する肺胞...
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| Published in | 日本胸部疾患学会雑誌 Vol. 34; no. 1; pp. 3 - 8 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English Japanese |
| Published |
社団法人 日本呼吸器学会
25.01.1996
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0301-1542 1883-471X |
| DOI | 10.11389/jjrs1963.34.3 |
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| Abstract | ブレオマイシンの細胞傷害を起こす機序は, DNA鎖の切断であると考えられている. そこでマウスのブレオマイシン肺臓炎を対象として, DNA断端の3'-OH基を組織上で特異的に検出可能な in situ biotin-dUTP end-labeling 法を用いてDNA傷害の局在と線維化との関連性を検討した. その結果, ブレオマイシン投与約1時間から12時間後は, 細気管支上皮細胞を中心にDNA傷害がみられ, その後回復するが, 徐々に線維化が進行すると共に肺胞上皮細胞のDNA傷害が増強し遷延していた. 投与直後のDNA傷害はステロイド投与によって影響を受けなかったが, 遷延する肺胞上皮細胞のDNA傷害は抑制され, 炎症による細胞傷害に伴うDNA傷害であると思われた. 組織上でDNA断端を標識し, 経時的にDNA傷害の局在の部位を解析することによって, ブレオマイシン肺臓炎の線維化の機序として遷延化する肺胞上皮のDNA傷害が重要であることが示唆された. |
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| AbstractList | ブレオマイシンの細胞傷害を起こす機序は, DNA鎖の切断であると考えられている. そこでマウスのブレオマイシン肺臓炎を対象として, DNA断端の3'-OH基を組織上で特異的に検出可能な in situ biotin-dUTP end-labeling 法を用いてDNA傷害の局在と線維化との関連性を検討した. その結果, ブレオマイシン投与約1時間から12時間後は, 細気管支上皮細胞を中心にDNA傷害がみられ, その後回復するが, 徐々に線維化が進行すると共に肺胞上皮細胞のDNA傷害が増強し遷延していた. 投与直後のDNA傷害はステロイド投与によって影響を受けなかったが, 遷延する肺胞上皮細胞のDNA傷害は抑制され, 炎症による細胞傷害に伴うDNA傷害であると思われた. 組織上でDNA断端を標識し, 経時的にDNA傷害の局在の部位を解析することによって, ブレオマイシン肺臓炎の線維化の機序として遷延化する肺胞上皮のDNA傷害が重要であることが示唆された. |
| Author | 萩本, 直樹 國武, 律子 原, 信之 野元, 吉二 橋本, 修一 桑野, 和善 |
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| References | 16) Pguet, P. F., Collart, M. A. & Grau, G. E.: Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med., 170: 655, 1989. 20) Khalil, N., Whitman, C., LiZuo, Danielpour, D., Greenberg, A.: Regulation of alveolar macrophage transforming growth factor-b secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat. J. Clin. Invest., 92: 1812, 1993. 1) Fleischman, R. W., Baber, J. R., Thompson, G. R., Schaeppi, U. H., Illievski, V. R., Cooney, D. A. & Davis, R. D.: Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26: 675, 1971. 3) Snider, G. L., Celli, B. R., Goldstein, R. H., Or-Brien, J. J. & Lucey, E. C.: Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Am. Rev. Respir. Dis., 117: 289, 1978. 13) Harrison, J. H. Jr. & Lazo, J. S.: Plasma and pulmonary pharmacokinetics of bleomycin in murine strains that are sensitive and resistant to bleomyin-induced pulmonary fibrosis. J. Pharmacol. Exp. Thr., 247: 1052, 1988. 18) Khalil, N., Bereznay, O. & Sporn,M.: Macrophage production of transforming growth factor b and fibroblast collagen synthesis in chronic pulmonary inflammation. J. Exp. Med., 170: 727, 1989. 12) Omar, T., Geraldine, P., Jean, B. Jr. & Mir, L. M.: Bleomycin, an Apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. Cancer Res., 53: 5462, 1993. 9) Sausville, E. A., Stein, R. W., Peisach, J. & Horowitz, S. B.: Properties and products of the degradation DNA by bleomycin and iron (II). Biochemistry, 17: 2746, 1978. 5) Terashima, T., Yasukawa, M. & Umezawa, M.: Beaks and rejoining of DNA in cultured mamalian cells treated with bleomycin. Gann, 61: 513, 1976. 8) Sugiura, Y.: The production of hydroxyl radical from copper (I) complex system of bleomycin and tallysomycin: Comparison with copper (II) and iron (II) systems. Biochem. Biophys. Res. Commun., 90: 375, 1979. 4) Thrall, R. S., Mccormick, J. R., Jack, R. M., McReynolds, R. A. & Ward, P. A.: Bleomycininduced pulmonary fibrosis in the rat. Inhibition with indomethacin. Am. J. Pathol., 95: 117, 1979. 6) Ishida, R. & Takahashi, T.: Increased DNA chain breakage by combined action of bleomycin and superoxide radical. Biochem. Biophys. Res. Commun., 66: 1432, 1975. 11) Hecht, S. M.: DNA strand scission by activated bleomycin group antibiotics. Fed. Proc., 45: 2784, 1986. 19) Kayanoki, Y., Fujii, J. & Suzuki, K.: Suppression of antioxidative enzyme expression by transforming growth factor-b1 in rat hepatocytes. J. Biol. Chem., 269: 15488, 1994. 10) Oberley, L. W. & Buettner, G. R.: The production of hydroxyl radical by bleomycin and iron (II). F. E. B. S. Lett., 97: 47, 1979. 15) Romanaga, F., Kulkarni, M. S. & Anderson, M. W.: Detection of repair of chemical-induced DNA damage in vivo by the nucleoid sedimentation assay. Biochem. Biophys. Res. Commun., 127: 56, 1985. 2) Adamson, I. Y. R. & Bowden, D. H.: The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am. J. Pathol., 77: 185, 1974. 14) Harrison, J. H. Jr., Hoyt, D. G. & Lazo, J. S.: Acute pulmonary toxicity of bleomycin: DNA scission and matrix protein mRNA levelsin bleomycin-sensitive and -resistant strains of mice. Mol. Pharmacol., 36: 231, 1989. 17) Jordana, M., Richards, C. & Irving, L. B.: Spontaneous in vitro release of alveolar macrophage cytokines after the intratracheal instillation of bleomycin in rats. Characterization and kinetic studies. Am. Rev. Respir. Dis.,137: 1135, 1988. 7) Gavrieli, Y., Sherman, Y. & Shmuel, A.: Identification of programmed cell death in site via specific labeling of nuclear DNA fragmentation. J. Cell Biol., 119: 493, 1992. |
| References_xml | – reference: 7) Gavrieli, Y., Sherman, Y. & Shmuel, A.: Identification of programmed cell death in site via specific labeling of nuclear DNA fragmentation. J. Cell Biol., 119: 493, 1992. – reference: 13) Harrison, J. H. Jr. & Lazo, J. S.: Plasma and pulmonary pharmacokinetics of bleomycin in murine strains that are sensitive and resistant to bleomyin-induced pulmonary fibrosis. J. Pharmacol. Exp. Thr., 247: 1052, 1988. – reference: 8) Sugiura, Y.: The production of hydroxyl radical from copper (I) complex system of bleomycin and tallysomycin: Comparison with copper (II) and iron (II) systems. Biochem. Biophys. Res. Commun., 90: 375, 1979. – reference: 11) Hecht, S. M.: DNA strand scission by activated bleomycin group antibiotics. Fed. Proc., 45: 2784, 1986. – reference: 17) Jordana, M., Richards, C. & Irving, L. B.: Spontaneous in vitro release of alveolar macrophage cytokines after the intratracheal instillation of bleomycin in rats. Characterization and kinetic studies. Am. Rev. Respir. Dis.,137: 1135, 1988. – reference: 19) Kayanoki, Y., Fujii, J. & Suzuki, K.: Suppression of antioxidative enzyme expression by transforming growth factor-b1 in rat hepatocytes. J. Biol. Chem., 269: 15488, 1994. – reference: 2) Adamson, I. Y. R. & Bowden, D. H.: The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am. J. Pathol., 77: 185, 1974. – reference: 14) Harrison, J. H. Jr., Hoyt, D. G. & Lazo, J. S.: Acute pulmonary toxicity of bleomycin: DNA scission and matrix protein mRNA levelsin bleomycin-sensitive and -resistant strains of mice. Mol. Pharmacol., 36: 231, 1989. – reference: 20) Khalil, N., Whitman, C., LiZuo, Danielpour, D., Greenberg, A.: Regulation of alveolar macrophage transforming growth factor-b secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat. J. Clin. Invest., 92: 1812, 1993. – reference: 3) Snider, G. L., Celli, B. R., Goldstein, R. H., Or-Brien, J. J. & Lucey, E. C.: Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Am. Rev. Respir. Dis., 117: 289, 1978. – reference: 5) Terashima, T., Yasukawa, M. & Umezawa, M.: Beaks and rejoining of DNA in cultured mamalian cells treated with bleomycin. Gann, 61: 513, 1976. – reference: 10) Oberley, L. W. & Buettner, G. R.: The production of hydroxyl radical by bleomycin and iron (II). F. E. B. S. Lett., 97: 47, 1979. – reference: 1) Fleischman, R. W., Baber, J. R., Thompson, G. R., Schaeppi, U. H., Illievski, V. R., Cooney, D. A. & Davis, R. D.: Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26: 675, 1971. – reference: 6) Ishida, R. & Takahashi, T.: Increased DNA chain breakage by combined action of bleomycin and superoxide radical. Biochem. Biophys. Res. Commun., 66: 1432, 1975. – reference: 9) Sausville, E. A., Stein, R. W., Peisach, J. & Horowitz, S. B.: Properties and products of the degradation DNA by bleomycin and iron (II). Biochemistry, 17: 2746, 1978. – reference: 18) Khalil, N., Bereznay, O. & Sporn,M.: Macrophage production of transforming growth factor b and fibroblast collagen synthesis in chronic pulmonary inflammation. J. Exp. Med., 170: 727, 1989. – reference: 15) Romanaga, F., Kulkarni, M. S. & Anderson, M. W.: Detection of repair of chemical-induced DNA damage in vivo by the nucleoid sedimentation assay. Biochem. Biophys. Res. Commun., 127: 56, 1985. – reference: 16) Pguet, P. F., Collart, M. A. & Grau, G. E.: Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med., 170: 655, 1989. – reference: 4) Thrall, R. S., Mccormick, J. R., Jack, R. M., McReynolds, R. A. & Ward, P. A.: Bleomycininduced pulmonary fibrosis in the rat. Inhibition with indomethacin. Am. J. Pathol., 95: 117, 1979. – reference: 12) Omar, T., Geraldine, P., Jean, B. Jr. & Mir, L. M.: Bleomycin, an Apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. Cancer Res., 53: 5462, 1993. |
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| SubjectTerms | DNA傷害 Terminal deoxynucleotidyl transferase mediated in situ biotion-dUTP end-labeling ブレオマイシン肺臓炎 |
| Title | ブレオマイシン肺臓炎における細気管支及び肺胞上皮細胞のDNA傷害 |
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