Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Oct;86(4):1055–1064. doi: 10.1172/JCI114808

Platelet-derived growth factor in idiopathic pulmonary fibrosis.

H N Antoniades 1, M A Bravo 1, R E Avila 1, T Galanopoulos 1, J Neville-Golden 1, M Maxwell 1, M Selman 1
PMCID: PMC296832  PMID: 2170444

Abstract

Fibrosis is a complex process involving an inflammatory reaction, fibroblast proliferation, and abnormal accumulation of interstitial collagens. Mononuclear cells are usually present in lung fibrosis. Activated monocytes and macrophages in culture have been shown to produce several growth factors including platelet-derived growth factor (PDGF). PDGF is a potent mitogen and chemoattractant for fibroblasts and smooth muscle cells and a stimulator of collagen synthesis. We have studied the expression of c-sis/PDGF-2 mRNA in lung tissues derived from five patients with idiopathic pulmonary fibrosis (IPF) and from four control individuals without IPF. Northern blot analysis of specimens obtained from four patients with IPF revealed the expression of the c-sis/PDGF-2 protooncogene. A control lung tissue without IPF did not express the c-sis protooncogene. In situ hybridization extended these studies demonstrating the expression of the c-sis mRNA in the five specimens with IPF but not in the four control specimens without IPF. The expression of c-sis mRNA was localized primarily in the epithelial cells. Invading alveolar macrophages also expressed c-sis mRNA. The expression of c-sis mRNA was accompanied by the expression of PDGF-like proteins in lung specimens with IPF but not in control lung specimens. These findings demonstrate the in vivo expression of the c-sis/PDGF-2 protooncogene and the production of PDGF-like proteins in the epithelial cells and macrophages of the fibrotic tissue. This localized and sustained production of PDGF-like mitogen may constitute an important contributing factor in the abnormal fibroblast proliferation and collagen production, events associated with pulmonary fibrosis.

Full text

PDF
1055

Images in this article

1056Image
on p.1056
1057Image
on p.1057
1058Image
on p.1058
1058Image
on p.1058
1059Image
on p.1059
1059Image
on p.1059
1060Image
on p.1060
1061Image
on p.1061
1062Image
on p.1062

Selected References

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

  1. Antoniades H. N., Hunkapiller M. W. Human platelet-derived growth factor (PDGF): amino-terminal amino acid sequence. Science. 1983 May 27;220(4600):963–965. doi: 10.1126/science.6844921. [DOI] [PubMed] [Google Scholar]
  2. Barrett T. B., Gajdusek C. M., Schwartz S. M., McDougall J. K., Benditt E. P. Expression of the sis gene by endothelial cells in culture and in vivo. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6772–6774. doi: 10.1073/pnas.81.21.6772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bauer E. A., Cooper T. W., Huang J. S., Altman J., Deuel T. F. Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4132–4136. doi: 10.1073/pnas.82.12.4132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernstein L. R., Antoniades H., Zetter B. R. Migration of cultured vascular cells in response to plasma and platelet-derived factors. J Cell Sci. 1982 Aug;56:71–82. doi: 10.1242/jcs.56.1.71. [DOI] [PubMed] [Google Scholar]
  5. Betsholtz C., Johnsson A., Heldin C. H., Westermark B., Lind P., Urdea M. S., Eddy R., Shows T. B., Philpott K., Mellor A. L. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature. 1986 Apr 24;320(6064):695–699. doi: 10.1038/320695a0. [DOI] [PubMed] [Google Scholar]
  6. Bitterman P. B., Adelberg S., Crystal R. G. Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J Clin Invest. 1983 Nov;72(5):1801–1813. doi: 10.1172/JCI111140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bronzert D. A., Pantazis P., Antoniades H. N., Kasid A., Davidson N., Dickson R. B., Lippman M. E. Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5763–5767. doi: 10.1073/pnas.84.16.5763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Collins T., Ginsburg D., Boss J. M., Orkin S. H., Pober J. S. Cultured human endothelial cells express platelet-derived growth factor B chain: cDNA cloning and structural analysis. Nature. 1985 Aug 22;316(6030):748–750. doi: 10.1038/316748a0. [DOI] [PubMed] [Google Scholar]
  9. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  10. Crystal R. G., Gadek J. E., Ferrans V. J., Fulmer J. D., Line B. R., Hunninghake G. W. Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am J Med. 1981 Mar;70(3):542–568. doi: 10.1016/0002-9343(81)90577-5. [DOI] [PubMed] [Google Scholar]
  11. Fulmer J. D. The interstitial lung diseases. Chest. 1982 Aug;82(2):172–178. doi: 10.1378/chest.82.2.172. [DOI] [PubMed] [Google Scholar]
  12. Gown A. M., Tsukada T., Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986 Oct;125(1):191–207. [PMC free article] [PubMed] [Google Scholar]
  13. Greenberg S. D., O'Neal R. M., Jenkins D. E. The pathologic findings in diffuse interstitial fibrosis of the lungs. South Med J. 1974 May;67(5):571–579. doi: 10.1097/00007611-197405000-00018. [DOI] [PubMed] [Google Scholar]
  14. Grotendorst G. R., Seppä H. E., Kleinman H. K., Martin G. R. Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3669–3672. doi: 10.1073/pnas.78.6.3669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Martinet Y., Bitterman P. B., Mornex J. F., Grotendorst G. R., Martin G. R., Crystal R. G. Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature. 1986 Jan 9;319(6049):158–160. doi: 10.1038/319158a0. [DOI] [PubMed] [Google Scholar]
  16. Martinet Y., Rom W. N., Grotendorst G. R., Martin G. R., Crystal R. G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987 Jul 23;317(4):202–209. doi: 10.1056/NEJM198707233170404. [DOI] [PubMed] [Google Scholar]
  17. Mornex J. F., Martinet Y., Yamauchi K., Bitterman P. B., Grotendorst G. R., Chytil-Weir A., Martin G. R., Crystal R. G. Spontaneous expression of the c-sis gene and release of a platelet-derived growth factorlike molecule by human alveolar macrophages. J Clin Invest. 1986 Jul;78(1):61–66. doi: 10.1172/JCI112574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pantazis P., Sariban E., Kufe D., Antoniades H. N. Induction of c-sis gene expression and synthesis of platelet-derived growth factor in human myeloid leukemia cells during monocytic differentiation. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6455–6459. doi: 10.1073/pnas.83.17.6455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ponte P., Ng S. Y., Engel J., Gunning P., Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984 Feb 10;12(3):1687–1696. doi: 10.1093/nar/12.3.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rennard S. I., Hunninghake G. W., Bitterman P. B., Crystal R. G. Production of fibronectin by the human alveolar macrophage: mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7147–7151. doi: 10.1073/pnas.78.11.7147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rozengurt E., Sinnett-Smith J., Taylor-Papadimitriou J. Production of PDGF-like growth factor by breast cancer cell lines. Int J Cancer. 1985 Aug 15;36(2):247–252. doi: 10.1002/ijc.2910360218. [DOI] [PubMed] [Google Scholar]
  22. Sariban E., Sitaras N. M., Antoniades H. N., Kufe D. W., Pantazis P. Expression of platelet-derived growth factor (PDGF)-related transcripts and synthesis of biologically active PDGF-like proteins by human malignant epithelial cell lines. J Clin Invest. 1988 Oct;82(4):1157–1164. doi: 10.1172/JCI113712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Selman M., Montaño M., Montfort I., Pérez-Tamayo R. A new model of diffuse interstitial pulmonary fibrosis in the rat. Exp Mol Pathol. 1985 Dec;43(3):375–387. doi: 10.1016/0014-4800(85)90074-7. [DOI] [PubMed] [Google Scholar]
  24. Selman M., Montaño M., Ramos C., Chapela R. Concentration, biosynthesis and degradation of collagen in idiopathic pulmonary fibrosis. Thorax. 1986 May;41(5):355–359. doi: 10.1136/thx.41.5.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Seppä H., Grotendorst G., Seppä S., Schiffmann E., Martin G. R. Platelet-derived growth factor in chemotactic for fibroblasts. J Cell Biol. 1982 Feb;92(2):584–588. doi: 10.1083/jcb.92.2.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
  27. Sitaras N. M., Sariban E., Bravo M., Pantazis P., Antoniades H. N. Constitutive production of platelet-derived growth factor-like proteins by human prostate carcinoma cell lines. Cancer Res. 1988 Apr 1;48(7):1930–1935. [PubMed] [Google Scholar]
  28. Sitaras N. M., Sariban E., Pantazis P., Zetter B., Antoniades H. N. Human iliac artery endothelial cells express both genes encoding the chains of platelet-derived growth factor (PDGF) and synthesize PDGF-like mitogen. J Cell Physiol. 1987 Aug;132(2):376–380. doi: 10.1002/jcp.1041320228. [DOI] [PubMed] [Google Scholar]
  29. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES