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. 1982 Feb;106(2):156–164.

The role of soluble factors in bleomycin-induced pulmonary fibrosis.

S H Phan, R S Thrall
PMCID: PMC1916179  PMID: 6175217

Abstract

Endotracheal administration of bleomycin causes pulmonary fibrosis characterized by increased collagen synthesis and deposition. Incubation of normal lung mince with neutral salt soluble extracts of lungs from normal and bleomycin-treated rats caused a dose-dependent inhibition of collagen and noncollagenous protein synthesis. Bleomycin-treated lung extracts, however, were significantly less effective in such inhibition when compared with normal lung extracts. This inhibitory activity was not diminished by dialysis in tubing with nominal molecular weight cutoff of 10,000 but was destroyed by heat (70 C) and trypsin digestion. This inhibitory activity could not be ascribed to residual serum or bleomycin in the lung extracts. Fractionation on Sephacryl S-200 (Pharmacia, Piscataway, NJ) showed inhibitory activity to be heterogeneous with Mr (apparent molecular weight) greater than 100,000. Extracts from spleen showed similar inhibitory activity but showed no difference in intensity between normal and bleomycin-treated spleen. These data suggest that loss or decrease in production of lung inhibitory regulatory factors is partly responsible for the noted increase in collagen production and deposition in bleomycin-induced pulmonary fibrosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson I. Y., Bowden D. H. The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol. 1974 Nov;77(2):185–197. [PMC free article] [PubMed] [Google Scholar]
  2. Baum B. J., Moss J., Breul S. D., Crystal R. G. Association in normal human fibroblasts of elevated levels of adenosine 3':5'-monophosphate with a selective decrease in collagen production. J Biol Chem. 1978 May 25;253(10):3391–3394. [PubMed] [Google Scholar]
  3. Bedrossian C. W., Greenberg S. D., Yawn D. H., O'Neal R. M. Experimentally induced bleomycin sulfate pulmonary toxicity: histopathologic and ultrastructural study in the pheasant. Arch Pathol Lab Med. 1977 May;101(5):248–254. [PubMed] [Google Scholar]
  4. Bradley K. H., McConnell S. D., Crystal R. G. Lung collagen composition and synthesis. Characterization and changes with age. J Biol Chem. 1974 May 10;249(9):2674–2683. [PubMed] [Google Scholar]
  5. Clark J. G., Starcher B. C., Uitto J. Bleomycin-induced synthesis of type I procollagen by human lung and skin fibroblasts in culture. Biochim Biophys Acta. 1980 Aug 13;631(2):359–370. doi: 10.1016/0304-4165(80)90309-8. [DOI] [PubMed] [Google Scholar]
  6. Fleischman R. W., Baker J. R., Thompson G. R., Schaeppi U. H., Illievski V. R., Cooney D. A., Davis R. D. Bleomycin-induced interstitial pneumonia in dogs. Thorax. 1971 Nov;26(6):675–682. doi: 10.1136/thx.26.6.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Jimenez S. A., McArthur W., Rosenbloom J. Inhibition of collagen synthesis by mononuclear cell supernates. J Exp Med. 1979 Dec 1;150(6):1421–1431. doi: 10.1084/jem.150.6.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Johnson R. L., Ziff M. Lymphokine stimulation of collagen accumulation. J Clin Invest. 1976 Jul;58(1):240–252. doi: 10.1172/JCI108455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Krous H. F., Hamlin W. B. Pulmonary toxicity due to bleomycin. Report of a case. Arch Pathol. 1973 Jun;95(6):407–410. [PubMed] [Google Scholar]
  10. Leibovich S. J., Ross R. A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol. 1976 Sep;84(3):501–514. [PMC free article] [PubMed] [Google Scholar]
  11. Luna M. A., Bedrossian C. W., Lichtiger B., Salem P. A. Interstitial pneumonitis associated with bleomycin therapy. Am J Clin Pathol. 1972 Nov;58(5):501–510. doi: 10.1093/ajcp/58.5.501. [DOI] [PubMed] [Google Scholar]
  12. Neilson E. G., Jimenez S. A., Phillips S. M. Cell-mediated immunity in interstitial nephritis. III. T lymphocyte-mediated fibroblast proliferation and collagen synthesis: an immune mechanism for renal fibrogenesis. J Immunol. 1980 Oct;125(4):1708–1714. [PubMed] [Google Scholar]
  13. Otsuka K., Murota S. I., Mori Y. Stimulatory effect of bleomycin on the synthesis of acidic glycosaminoglycans in cultured fibroblasts derived from rat carrageenin granuloma. Biochim Biophys Acta. 1976 Sep 24;444(2):359–368. doi: 10.1016/0304-4165(76)90379-2. [DOI] [PubMed] [Google Scholar]
  14. Peterkofsky B., Diegelmann R. Use of a mixture of proteinase-free collagenases for the specific assay of radioactive collagen in the presence of other proteins. Biochemistry. 1971 Mar 16;10(6):988–994. doi: 10.1021/bi00782a009. [DOI] [PubMed] [Google Scholar]
  15. Phan S. H., Thrall R. S., Ward P. A. Bleomycin-induced pulmonary fibrosis in rats: biochemical demonstration of increased rate of collagen synthesis. Am Rev Respir Dis. 1980 Mar;121(3):501–506. doi: 10.1164/arrd.1980.121.3.501. [DOI] [PubMed] [Google Scholar]
  16. Raisz L. G., Koolemans-Beynen A. R. Inhibition of bone collagen synthesis by prostaglandin E2 in organ culture. Prostaglandins. 1974 Dec 10;8(5):377–385. doi: 10.1016/0090-6980(74)90113-0. [DOI] [PubMed] [Google Scholar]
  17. Snider G. L., Celli B. R., Goldstein R. H., O'Brien J. J., Lucey E. C. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. Am Rev Respir Dis. 1978 Feb;117(2):289–297. doi: 10.1164/arrd.1978.117.2.289. [DOI] [PubMed] [Google Scholar]
  18. Thrall R. S., McCormick J. R., Jack R. M., McReynolds R. A., Ward P. A. Bleomycin-induced pulmonary fibrosis in the rat: inhibition by indomethacin. Am J Pathol. 1979 Apr;95(1):117–130. [PMC free article] [PubMed] [Google Scholar]
  19. Wahl S. M., Wahl L. M., McCarthy J. B. Lymphocyte-mediated activation of fibroblast proliferation and collagen production. J Immunol. 1978 Sep;121(3):942–946. [PubMed] [Google Scholar]

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