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Radiation-induced lung injury in vivo: Expression of transforming growth factor—Beta precedes fibrosis

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Abstract

Cytokine release from irradiated cells has been postulated to start soon after irradiation preceding detectable clinical and pathological manifestation of lung injury. The expression of transforming growth factor beta (TGFβ), a fibrogenic and radiation-inducible cytokine, was studied from 1–16 weeks after the 15 and 30 Gray (Gy) of thoracic irradiation to rats. Thoracic irradiation caused an increase in TGFβ protein in bronchoalveolar lavage (BAL) fluid peaking at 3–6 weeks as compared to sham-irradiated control rats. Steady state TGFβ mRNA expression as shown by whole lung northern blot assay paralleled the TGFβ protein expression in BAL fluid. The peak of TGFβ protein increase in BAL fluid between 3 and 6 weeks coincided with the initial influx of inflammatory cells in BAL fluid, but preceded histologically discernable pulmonary fibrosis that was not apparent until 8–10 weeks after irradiation. In conclusion, TGFβ and mRNA and protein upregulation preceded the radiation-induced pulmonary fibrosis, suggesting a pathogenetic role in the development of radiation fibrosis.

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References

  1. Rubin, P., L. S. Constine, andD. F. Nelson, 1992. Late effects of cancer treatment: radiation and drug toxicity.In C. A. Perez, and L. W. Brady, editors. Principles and practices of radiation oncology, 2nd ed. J. B. Lippincott, New York. 131–134.

    Google Scholar 

  2. Hallahan, D. E., A. Haimovitz-Friedman, D. W. Kufe, Z. Fuks, andR. R. Weichselbaum. 1993.In The role of cytokines in radiation oncology. Important advances in oncology, V. T. DeVita, S. Hellman, and S. A. Rosenberg, editors. J. B. Lippincott, New York. pp. 71–80.

    Google Scholar 

  3. Witte, L., Z. Fuks, A. Haimovitz-Friedman, I. Vlodavsky, D. S. Goodman, andA. Eldor. 1989. Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells.Cancer Res. 49:5066–5072.

    Google Scholar 

  4. Rubin, P., J. Finkelstein, andD. Shapiro. 1992. Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes. Interrelationship between the alveolar macrophages and the septal fibroblast.Int. J. Radiation Oncology Biol. Phys. 24:92–101.

    Google Scholar 

  5. Rosiello, R. A., W. W. Merrill, D. Rockwell, D. Carter, J. A. D. Cooper, S. Care, andE. P. Amento. 1993. Radiation pneumonitis. Bronchoalveolar lavage assessment and modulation by a recombinant cytokine.Am. Rev. Respir. Dis. 148:1671–1676.

    Google Scholar 

  6. Barcellos-Hoff, M. H., R. Derynck, M. L. S. Tsang, andJ. A. Weatherbee. 1994. Transforming growth factor beta activation in irradiation murine mammary gland.J. Clin. Invest. 93:892–899.

    Google Scholar 

  7. Anscher, M. S., T. Murase, D. M. Prescott, L. B. Marks, H. Reisenbichler, G. C. Bentel, D. Spencer, G. Sherouse, andR. L. Jirtle. 1994. Changes in plasma TGFbeta level during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis.Int. J. Radiation Oncology Biol. Phys. 30:671–676.

    Google Scholar 

  8. Finkelstein, J. N., C. J. Johnston, R. Baggs, andP. Rubin. 1994. Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis.Int. J. Radiation Oncology Biol. Phys. 28:621–631.

    Google Scholar 

  9. Ulich, T. R., L. R. Watson, S. Yin, K. Guo, P. Wang, H. Thang, andJ. del Castillo. 1991. The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS- induced IL-1 and TNF and mRNA expression and the LPS-, IL-1, and TNF-induced inflammatory infiltrate.Am. J. Pathol. 138:1485–1496.

    Google Scholar 

  10. Danielpour, D., K. Y. Kim, L. L. Dart, S. Watanabe, A. B. Roberts, andM. B. Sporn. 1989. Sandwich enzyme-linked immunosorbent assays (SELISAs) quantitate and distinguish two forms of transforming growth factor-beta (TGFβ1 and TGF-β2) in complex biological fluids.Growth Factors 2:61–71.

    Google Scholar 

  11. Chomczynski, P., andN. Sacchi. 1987. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction.Anal. Biochem. 162:156–159.

    Google Scholar 

  12. Qian, S. W., P. Kondaiah, A. B. Roberts, andM. B. Sporn. 1990. cDNA cloning by PCR of rat transforming growth factor beta-1.Nucleic Acids Res. 18:3059.

    Google Scholar 

  13. Hsu, S. M., L. Raine, andH. Fanger. 1981. The use of antiavidin antibody and anti-biotin-peroxidase complex in immunoperoxidase techniques.Am. J. Clin. Pathol. 75:816–821.

    Google Scholar 

  14. Phan, S. H., andS. L. Kunkel. 1992. Lung cytokine production in bleomycin-induced pulmonary fibrosis.Exp. Lung Research 18:29–43.

    Google Scholar 

  15. Kelley, J. 1993. Transforming growth factor beta.In Cytokines of the Lung, 1st ed., J. Kelley, editor. Marcel Dekker, New York. 101–137.

    Google Scholar 

  16. Raghow, R., P. Irish, andA. H. Kang. 1989. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycininduced pulmonary fibrosis.J. Clin. Invest. 84:1836–1842.

    Google Scholar 

  17. Breen, E., S. Shull, S. Burne, M. Absher, J. Kelley, S. Phan, andK. R. Cutroneo. 1992. Bleomycin regulation of transforming growth factor-beta mRNA in rat lung fibroblasts.Am. J. Res. Cell Mol. Biol. 6:146–152.

    Google Scholar 

  18. Khalil, N., R. N. O'Connor, K. C. Flanders, W. Shing, andC. I. Whitman. 1994. Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats.Am. J. Physiol. 267:L498–507.

    Google Scholar 

  19. Giri, S. N., D. M. Hyde, andM. A. Hollinger. 1993. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice.Thorax 8:959–966.

    Google Scholar 

  20. Westergren-Thprsson, G., J. Hernnas, B. Sarnstrand, A. Oldberg, D. Heinegard, andA. Malmstrom. 1993. Altered expression of small proteoglycans, collagen, and transforming growth factor-beta 1 in developing bleomycin-induced pulmonary fibrosis in rats.J. Clin. Invest. 92:632–637.

    Google Scholar 

  21. Hoyt, D. G., andJ. S. Lazo. 1990. Bleomycin and cyclophosphamide increase pulmonary type IV collagen mRNA in mice.Am. J. Physiol. 259:L47-L52.

    Google Scholar 

  22. Khalil, N., O. Bereznay, M. Sporn, andA. H. Greenberg. 1989. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary fibrosis.J. Exp. Med. 170:727–737.

    Google Scholar 

  23. Limper, A. H., T. J. Broekelmann, T. V. Colby, G. Malizia, andJ. A. McDonald. 1991. Analysis of local mRNA expression of extracellular matrix proteins and growth factors using in situ hybridization fibroproliferative lung disorders.Chest 99:55S-56S.

    Google Scholar 

  24. Khalil, N., R. N. O'Connor, H. W. Unruh, P. W. Warren, K. C. Flanders, A. Kemp, O. H. Bereznay, andA. H. Greenberg. 1991. Increased production and immunohistochemical localization of transforming growth factor beta in idiopathic pulmonary fibrosis.Am. J. Resp. Cell Mol. Biol. 5:155–162.

    Google Scholar 

  25. McDonald, S., P. Rubin, andP. Maasilta. 1989. Response of normal lung to irradiation. Tolerance doses/tolerance volumes in pulmonary radiation syndromes.In Radiation tolerance of normal tissues, J. M. Vaeth, and J. L. Meyer, editors. Karger, Basel. 255–276.

    Google Scholar 

  26. Veragara, J. A., U. Raymond, andL. A. Thet. 1986. Changes in lung morphology and cell number in radiation pneumonitis and fibrosis: A quantitative ultrastructural study.Int. J. Radiation Oncol. Biol. Phys. 13:723–732.

    Google Scholar 

  27. Rubin, P., S. McDonald, P. Maasilta, J. N. Finkelstein, D. L. Shapiro, D. Penney, andP. K. Gregory. 1989. Serum markers for production of pulmonary radiation syndromes. Part I: Surfactant apoprotein.Int. J. Radiation Oncol. Biol. Phys. 17:553–558.

    Google Scholar 

  28. Ulich, T. R., E. S. Yi, K. Longmuir, S. Yin, R. Blitz, C. Morris, R. M. Housley, andG. F. Pierce. 1994. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo.J. Clin. Invest. 93:1298–1306.

    Google Scholar 

  29. Deterding, R. R., T. Yano, A. M. Havill, C. R. Jacoby, J. M. Shannon, W. S. Simonet, andR. J. Mason. 1995. Keratinocyte growth factor prevents bleomycin lung injury in rats.Am. J. Resp. Crit. Care Med. 151:A198.

    Google Scholar 

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Yi, E.S., Bedoya, A., Lee, H. et al. Radiation-induced lung injury in vivo: Expression of transforming growth factor—Beta precedes fibrosis. Inflammation 20, 339–352 (1996). https://doi.org/10.1007/BF01486737

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