Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Aug 1;88(15):6642–6646. doi: 10.1073/pnas.88.15.6642

Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis.

T J Broekelmann 1, A H Limper 1, T V Colby 1, J A McDonald 1
PMCID: PMC52144  PMID: 1862087

Abstract

Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, we demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, we now demonstrate the presence of transforming growth factor beta 1 (TGF-beta 1), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-beta 1 may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-beta 1 is the alveolar macrophage, and we demonstrate the expression of abundant TGF-beta 1 mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

Full text

PDF
6642

Images in this article

Selected References

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

  1. Adachi K., Yamauchi K., Bernaudin J. F., Fouret P., Ferrans V. J., Crystal R. G. Evaluation of fibronectin gene expression by in situ hybridization. Differential expression of the fibronectin gene among populations of human alveolar macrophages. Am J Pathol. 1988 Nov;133(2):193–203. [PMC free article] [PubMed] [Google Scholar]
  2. Andres J. L., Stanley K., Cheifetz S., Massagué J. Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta. J Cell Biol. 1989 Dec;109(6 Pt 1):3137–3145. doi: 10.1083/jcb.109.6.3137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Assoian R. K., Sporn M. B. Type beta transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J Cell Biol. 1986 Apr;102(4):1217–1223. doi: 10.1083/jcb.102.4.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Border W. A., Okuda S., Languino L. R., Sporn M. B., Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature. 1990 Jul 26;346(6282):371–374. doi: 10.1038/346371a0. [DOI] [PubMed] [Google Scholar]
  7. Boyd C. D., Kniep A. C., Pierce R. A., Deak S. B., Karboski C., Miller D. C., Parker M. I., Mackenzie J. W., Rosenbloom J., Scott G. E. Increased elastin mRNA levels associated with surgically induced intimal injury. Connect Tissue Res. 1988;18(2):65–78. doi: 10.3109/03008208809008059. [DOI] [PubMed] [Google Scholar]
  8. Childs C. B., Proper J. A., Tucker R. F., Moses H. L. Serum contains a platelet-derived transforming growth factor. Proc Natl Acad Sci U S A. 1982 Sep;79(17):5312–5316. doi: 10.1073/pnas.79.17.5312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dean D. C., Newby R. F., Bourgeois S. Regulation of fibronectin biosynthesis by dexamethasone, transforming growth factor beta, and cAMP in human cell lines. J Cell Biol. 1988 Jun;106(6):2159–2170. doi: 10.1083/jcb.106.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Derynck R., Jarrett J. A., Chen E. Y., Eaton D. H., Bell J. R., Assoian R. K., Roberts A. B., Sporn M. B., Goeddel D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. doi: 10.1038/316701a0. [DOI] [PubMed] [Google Scholar]
  11. Diaz A., Varga J., Jimenez S. A. Transforming growth factor-beta stimulation of lung fibroblast prostaglandin E2 production. J Biol Chem. 1989 Jul 15;264(20):11554–11557. [PubMed] [Google Scholar]
  12. Fine A., Goldstein R. H. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem. 1987 Mar 15;262(8):3897–3902. [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Hoyt D. G., Lazo J. S. Early increases in pulmonary mRNA encoding procollagens and transforming growth factor-beta in mice sensitive to cyclophosphamide-induced pulmonary fibrosis. J Pharmacol Exp Ther. 1989 Apr;249(1):38–43. [PubMed] [Google Scholar]
  16. Idell S., Gonzalez K. K., MacArthur C. K., Gillies C., Walsh P. N., McLarty J., Thrall R. S. Bronchoalveolar lavage procoagulant activity in bleomycin-induced lung injury in marmosets. Characterization and relationship to fibrin deposition and fibrosis. Am Rev Respir Dis. 1987 Jul;136(1):124–133. doi: 10.1164/ajrccm/136.1.124. [DOI] [PubMed] [Google Scholar]
  17. Ignotz R. A., Endo T., Massagué J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987 May 15;262(14):6443–6446. [PubMed] [Google Scholar]
  18. Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. doi: 10.1164/ajrccm/141.3.765. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Kornblihtt A. R., Umezawa K., Vibe-Pedersen K., Baralle F. E. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J. 1985 Jul;4(7):1755–1759. doi: 10.1002/j.1460-2075.1985.tb03847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kuhn C., 3rd, Boldt J., King T. E., Jr, Crouch E., Vartio T., McDonald J. A. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis. 1989 Dec;140(6):1693–1703. doi: 10.1164/ajrccm/140.6.1693. [DOI] [PubMed] [Google Scholar]
  22. Kuhn C., McDonald J. A. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol. 1991 May;138(5):1257–1265. [PMC free article] [PubMed] [Google Scholar]
  23. McDonald J. A., Broekelmann T. J., Matheke M. L., Crouch E., Koo M., Kuhn C., 3rd A monoclonal antibody to the carboxyterminal domain of procollagen type I visualizes collagen-synthesizing fibroblasts. Detection of an altered fibroblast phenotype in lungs of patients with pulmonary fibrosis. J Clin Invest. 1986 Nov;78(5):1237–1244. doi: 10.1172/JCI112707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mooradian D. L., Lucas R. C., Weatherbee J. A., Furcht L. T. Transforming growth factor-beta 1 binds to immobilized fibronectin. J Cell Biochem. 1989 Dec;41(4):189–200. doi: 10.1002/jcb.240410404. [DOI] [PubMed] [Google Scholar]
  25. Okuda S., Languino L. R., Ruoslahti E., Border W. A. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest. 1990 Aug;86(2):453–462. doi: 10.1172/JCI114731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Prosser I. W., Stenmark K. R., Suthar M., Crouch E. C., Mecham R. P., Parks W. C. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol. 1989 Dec;135(6):1073–1088. [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Raghow R., Postlethwaite A. E., Keski-Oja J., Moses H. L., Kang A. H. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest. 1987 Apr;79(4):1285–1288. doi: 10.1172/JCI112950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Roberts C. J., Birkenmeier T. M., McQuillan J. J., Akiyama S. K., Yamada S. S., Chen W. T., Yamada K. M., McDonald J. A. Transforming growth factor beta stimulates the expression of fibronectin and of both subunits of the human fibronectin receptor by cultured human lung fibroblasts. J Biol Chem. 1988 Apr 5;263(10):4586–4592. [PubMed] [Google Scholar]
  31. Varga J., Jimenez S. A. Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-beta. Biochem Biophys Res Commun. 1986 Jul 31;138(2):974–980. doi: 10.1016/s0006-291x(86)80591-5. [DOI] [PubMed] [Google Scholar]
  32. Yamaguchi Y., Mann D. M., Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature. 1990 Jul 19;346(6281):281–284. doi: 10.1038/346281a0. [DOI] [PubMed] [Google Scholar]
  33. Yamauchi K., Martinet Y., Basset P., Fells G. A., Crystal R. G. High levels of transforming growth factor-beta are present in the epithelial lining fluid of the normal human lower respiratory tract. Am Rev Respir Dis. 1988 Jun;137(6):1360–1363. doi: 10.1164/ajrccm/137.6.1360. [DOI] [PubMed] [Google Scholar]
  34. Yang E. Y., Moses H. L. Transforming growth factor beta 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol. 1990 Aug;111(2):731–741. doi: 10.1083/jcb.111.2.731. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES