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. 1993 Jun;142(6):1831–1840.

Immunohistochemical localization of transforming growth factor-beta 1 in rats with experimental silicosis, alveolar type II hyperplasia, and lung cancer.

A O Williams 1, K C Flanders 1, U Saffiotti 1
PMCID: PMC1887001  PMID: 8389528

Abstract

Immunohistochemical localization of transforming growth factor-beta 1 (TGF-beta 1) was studied in the lungs of rats given crystalline silica or ferric oxide by single intratracheal instillation. Ferric oxide elicited no progressive granulomatous reaction, no epithelial hyperplasia, and no lung tumors; no demonstrable reactivity to TGF-beta 1 was observed. Silica induced a granulomatous reaction with progressive fibrosis, adjacent alveolar type II hyperplasia, and alveolar carcinomas. Rabbit polyclonal antibodies to synthetic peptides corresponding to the first 30 amino acids of mature TGF-beta 1, anti-LC (1-30), and anti-CC (1-30) were used for the localization of intracellular and extracellular TGF-beta 1. An antibody to a peptide corresponding to amino acids 266-278 of the TGF-beta 1 precursor sequence, anti-Pre (266-278), was used to detect the TGF-beta precursor and the latency-associated peptide. Intracellular mature TGF-beta (anti-LC) was demonstrated in fibroblasts and macrophages located at the periphery of silicotic granulomas and in fibroblasts adjacent to hyperplastic type II cells. Extracellular mature TGF-beta 1 was localized in the connective tissue matrix of the granulomas and in the stroma of both hyperplastic type II cells and well-differentiated adenocarcinomas. Immunoreactivity to anti-Pre was localized, intracellularly, in hyperplastic alveolar type II cells and their proliferative lesions adjacent to granulomas, in adenomas, but not in adenocarcinomas. The hyperplastic type II cells appear to be the sites of production and secretion of TGF-beta 1, which may regulate their own growth and differentiation and mediate the production of extracellular TGF-beta 1-associated matrix. The lack of reactivity to TGF-beta 1 precursor in the adenocarcinomas is consistent with the loss of normal cellular differentiation and function. TGF-beta 1 appears to have a pathogenetic role in silica-induced mesenchymal and epithelial lesions. The role of TGF-beta 1 and other cytokines in silica-induced carcinogenesis requires further investigation.

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Selected References

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

  1. Antonelli-Orlidge A., Saunders K. B., Smith S. R., D'Amore P. A. An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4544–4548. doi: 10.1073/pnas.86.12.4544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Braun L., Mead J. E., Panzica M., Mikumo R., Bell G. I., Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1539–1543. doi: 10.1073/pnas.85.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Castilla A., Prieto J., Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med. 1991 Apr 4;324(14):933–940. doi: 10.1056/NEJM199104043241401. [DOI] [PubMed] [Google Scholar]
  4. Connor T. B., Jr, Roberts A. B., Sporn M. B., Danielpour D., Dart L. L., Michels R. G., de Bustros S., Enger C., Kato H., Lansing M. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J Clin Invest. 1989 May;83(5):1661–1666. doi: 10.1172/JCI114065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Czaja M. J., Weiner F. R., Flanders K. C., Giambrone M. A., Wind R., Biempica L., Zern M. A. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol. 1989 Jun;108(6):2477–2482. doi: 10.1083/jcb.108.6.2477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DiMari S. J., Howe A. M., Haralson M. A. Effects of transforming growth factor-beta on collagen synthesis by fetal rat lung epithelial cells. Am J Respir Cell Mol Biol. 1991 May;4(5):455–462. doi: 10.1165/ajrcmb/4.5.455. [DOI] [PubMed] [Google Scholar]
  7. Driscoll K. E., Lindenschmidt R. C., Maurer J. K., Higgins J. M., Ridder G. Pulmonary response to silica or titanium dioxide: inflammatory cells, alveolar macrophage-derived cytokines, and histopathology. Am J Respir Cell Mol Biol. 1990 Apr;2(4):381–390. doi: 10.1165/ajrcmb/2.4.381. [DOI] [PubMed] [Google Scholar]
  8. Flanders K. C., Thompson N. L., Cissel D. S., Van Obberghen-Schilling E., Baker C. C., Kass M. E., Ellingsworth L. R., Roberts A. B., Sporn M. B. Transforming growth factor-beta 1: histochemical localization with antibodies to different epitopes. J Cell Biol. 1989 Feb;108(2):653–660. doi: 10.1083/jcb.108.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heine U., Munoz E. F., Flanders K. C., Ellingsworth L. R., Lam H. Y., Thompson N. L., Roberts A. B., Sporn M. B. Role of transforming growth factor-beta in the development of the mouse embryo. J Cell Biol. 1987 Dec;105(6 Pt 2):2861–2876. doi: 10.1083/jcb.105.6.2861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hesterberg T. W., Barrett J. C. Dependence of asbestos- and mineral dust-induced transformation of mammalian cells in culture on fiber dimension. Cancer Res. 1984 May;44(5):2170–2180. [PubMed] [Google Scholar]
  11. Hoyt D. G., Lazo J. S. Alterations in pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor-beta precede bleomycin-induced pulmonary fibrosis in mice. J Pharmacol Exp Ther. 1988 Aug;246(2):765–771. [PubMed] [Google Scholar]
  12. Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
  13. Jetten A. M., Shirley J. E., Stoner G. Regulation of proliferation and differentiation of respiratory tract epithelial cells by TGF beta. Exp Cell Res. 1986 Dec;167(2):539–549. doi: 10.1016/0014-4827(86)90193-x. [DOI] [PubMed] [Google Scholar]
  14. Johnson N. F., Smith D. M., Sebring R., Holland L. M. Silica-induced alveolar cell tumors in rats. Am J Ind Med. 1987;11(1):93–107. doi: 10.1002/ajim.4700110110. [DOI] [PubMed] [Google Scholar]
  15. Kampschmidt R. F., Worthington M. L., 3rd, Mesecher M. I. Release of interleukin-1 (IL-1) and IL-1-like factors from rabbit macrophages with silica. J Leukoc Biol. 1986 Feb;39(2):123–132. doi: 10.1002/jlb.39.2.123. [DOI] [PubMed] [Google Scholar]
  16. Khalil N., Bereznay O., Sporn M., Greenberg A. H. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med. 1989 Sep 1;170(3):727–737. doi: 10.1084/jem.170.3.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Khalil N., O'Connor R. N., Unruh H. W., Warren P. W., Flanders K. C., Kemp A., Bereznay O. H., Greenberg A. H. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 1991 Aug;5(2):155–162. doi: 10.1165/ajrcmb/5.2.155. [DOI] [PubMed] [Google Scholar]
  18. Laurent G. J., Harrison N. K., McAnulty R. J. The regulation of collagen production in normal lung and during interstitial lung disease. Postgrad Med J. 1988;64 (Suppl 4):26–34. [PubMed] [Google Scholar]
  19. McCune B. K., Mullin B. R., Flanders K. C., Jaffurs W. J., Mullen L. T., Sporn M. B. Localization of transforming growth factor-beta isotypes in lesions of the human breast. Hum Pathol. 1992 Jan;23(1):13–20. doi: 10.1016/0046-8177(92)90004-m. [DOI] [PubMed] [Google Scholar]
  20. McMahon J. B., Richards W. L., del Campo A. A., Song M. K., Thorgeirsson S. S. Differential effects of transforming growth factor-beta on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res. 1986 Sep;46(9):4665–4671. [PubMed] [Google Scholar]
  21. Miller B. E., Dethloff L. A., Gladen B. C., Hook G. E. Progression of type II cell hypertrophy and hyperplasia during silica-induced pulmonary inflammation. Lab Invest. 1987 Nov;57(5):546–554. [PubMed] [Google Scholar]
  22. Muhle H., Takenaka S., Mohr U., Dasenbrock C., Mermelstein R. Lung tumor induction upon long-term low-level inhalation of crystalline silica. Am J Ind Med. 1989;15(3):343–346. doi: 10.1002/ajim.4700150309. [DOI] [PubMed] [Google Scholar]
  23. Oghiso Y., Kubota Y. Enhanced interleukin 1 production by alveolar macrophages and increase in Ia-positive lung cells in silica-exposed rats. Microbiol Immunol. 1986;30(11):1189–1198. doi: 10.1111/j.1348-0421.1986.tb03047.x. [DOI] [PubMed] [Google Scholar]
  24. Piguet P. F., Collart M. A., Grau G. E., Sappino A. P., Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990 Mar 15;344(6263):245–247. doi: 10.1038/344245a0. [DOI] [PubMed] [Google Scholar]
  25. Raghow B., Irish P., Kang A. H. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J Clin Invest. 1989 Dec;84(6):1836–1842. doi: 10.1172/JCI114369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rannels S. R., Rannels D. E. The type II pneumocyte as a model of lung cell interaction with the extracellular matrix. J Mol Cell Cardiol. 1989 Feb;21 (Suppl 1):151–159. doi: 10.1016/0022-2828(89)90851-1. [DOI] [PubMed] [Google Scholar]
  27. Roberts A. B., Flanders K. C., Kondaiah P., Thompson N. L., Van Obberghen-Schilling E., Wakefield L., Rossi P., de Crombrugghe B., Heine U., Sporn M. B. Transforming growth factor beta: biochemistry and roles in embryogenesis, tissue repair and remodeling, and carcinogenesis. Recent Prog Horm Res. 1988;44:157–197. doi: 10.1016/b978-0-12-571144-9.50010-7. [DOI] [PubMed] [Google Scholar]
  28. Roberts A. B., Frolik C. A., Anzano M. A., Sporn M. B. Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc. 1983 Jun;42(9):2621–2626. [PubMed] [Google Scholar]
  29. Roberts A. B., Heine U. I., Flanders K. C., Sporn M. B. Transforming growth factor-beta. Major role in regulation of extracellular matrix. Ann N Y Acad Sci. 1990;580:225–232. doi: 10.1111/j.1749-6632.1990.tb17931.x. [DOI] [PubMed] [Google Scholar]
  30. Roberts A. B., Sporn M. B., Assoian R. K., Smith J. M., Roche N. S., Wakefield L. M., Heine U. I., Liotta L. A., Falanga V., Kehrl J. H. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. doi: 10.1073/pnas.83.12.4167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roberts A. B., Thompson N. L., Heine U., Flanders C., Sporn M. B. Transforming growth factor-beta: possible roles in carcinogenesis. Br J Cancer. 1988 Jun;57(6):594–600. doi: 10.1038/bjc.1988.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sato Y., Tsuboi R., Lyons R., Moses H., Rifkin D. B. Characterization of the activation of latent TGF-beta by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J Cell Biol. 1990 Aug;111(2):757–763. doi: 10.1083/jcb.111.2.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schmidt J. A., Oliver C. N., Lepe-Zuniga J. L., Green I., Gery I. Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin 1. A potential role for interleukin 1 in the pathogenesis of silicosis. J Clin Invest. 1984 May;73(5):1462–1472. doi: 10.1172/JCI111350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sporn M. B., Roberts A. B. Peptide growth factors are multifunctional. Nature. 1988 Mar 17;332(6161):217–219. doi: 10.1038/332217a0. [DOI] [PubMed] [Google Scholar]
  35. Varga J., Rosenbloom J., Jimenez S. A. Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J. 1987 Nov 1;247(3):597–604. doi: 10.1042/bj2470597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wagner M. M., Wagner J. C., Davies R., Griffiths D. M. Silica-induced malignant histiocytic lymphoma: incidence linked with strain of rat and type of silica. Br J Cancer. 1980 Jun;41(6):908–917. doi: 10.1038/bjc.1980.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wakefield L. M., Smith D. M., Flanders K. C., Sporn M. B. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J Biol Chem. 1988 Jun 5;263(16):7646–7654. [PubMed] [Google Scholar]

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