Skip to main content
Log in

Direct measurement of IGF-I and IGFBP-3 in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the rearrangement of extracellular matrix and progressive increase in the amount of fibrotic tissue in the lung. IGF-I is a potent profibrogenic molecule and its bioavailability is dependent on at least 6 binding proteins called IGFBPs. Among these, IGFBP-3 is the most represented in serum and in different connective tissues. The purpose of this study was to identify and characterize IGFBP-3 in bronchoalveolar lavage (BAL) fluids. We studied 11 patients with IPF and 6 normal subjects by performing baseline pulmonary function test and BAL. IGF-I and IGFBP-3 were measured by RIA in BAL and serum. No significant differences were observed between serum IGF-I and IGFBP-3 from IPF patients and normal subjects. Instead, the direct measurement in BAL revealed a significant increase of IGF-I and IGFBP-3 in IPF patients compared to normal subjects. BAL IGF-I and IGFBP-3 concentrations were significantly related to inspiratory vital capacity (IVC) and carbon dioxide partial pressure (PaCO2): the higher the value of IVC and the lower the value of PaCO2, the higher the level of IGF-I and IGFBP-3. In conclusion, IGFBP3 and IGF-I could be important local mediators of IPF. Their direct measurement in BAL in IPF patients could be used as a clinical marker of the disease, since high levels of IGFBP-3 and IGF-I in BAL are associated to the initial phase of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jones J.I., Clemmons D.R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 1995, 16: 3–34.

    CAS  PubMed  Google Scholar 

  2. Rechler M.M. Insulin-like growth factor binding proteins. Vitam. Horm. 1993, 47: 1–114.

    Article  CAS  PubMed  Google Scholar 

  3. Shimasaki S., Ling N. Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5, -6). Progr. Growth Factor Res. 1991, 3: 243–266.

    Article  CAS  Google Scholar 

  4. Kim H.S., Nagalla S.R, OH Y., Wilson E., Roberts C.T. Jr., Rosenfeld R.G. Identification of a family of low affinity insulin-like growth factor binding proteins (IGFBPs), characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Natl. Acad. Sci. USA 1997, 94: 12981–12986.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Baxter R.C. Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex. J. Clin. Endocrinol. Metab. 1988, 67: 265–272.

    Article  CAS  PubMed  Google Scholar 

  6. Clemmons D.R. Insulin-like growth factor binding proteins control secretion and mechanism of action. Adv. Exp. Med. Biol. 1991, 293: 113–123.

    Article  CAS  PubMed  Google Scholar 

  7. Giannini S., Maggi M., Cresci B., Fusetti G., Bonaccorsi L., Luconi M., Rotella C.M., Forti G., Serio M., Baldi E. Platelet activating factor enhances production of insulin-like growth factor binding proteins in a human adenocarcinoma cell line. Gynecol. Oncol. 1996, 61: 333–340.

    Article  CAS  PubMed  Google Scholar 

  8. Giannini S., Mohan S., Kasuya J., Galli G., Rotella C.M., Le Bon T.R., Fujita-Yamaguchi Y. Characterization of insulin-like growth factor binding proteins produced by cultured fibroblasts from patients with non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus or obesity. J. Clin. Endocrinol. Metab. 1994, 79: 1824–1830.

    CAS  PubMed  Google Scholar 

  9. Giannini S., Cresci B., Manuelli C., Fujita-Yamaguchi Y., Romagnani P., Mohan S., Rotella C.M. Insulin-like growth factor binding protein production in bovine retinal cells. Metabolism 1997, 46: 1367–1379.

    Article  CAS  PubMed  Google Scholar 

  10. Mc-Cusker R.H., Busby W.H., Dehof M.H., Camacho-Hubner C., Clemmons D.R. Insulin-like growth factor (IGF) binding to cell monolayers is directly modulated by the addition of IGFbinding proteins. Endocrinology 1991, 129: 2631–2638.

    Article  CAS  Google Scholar 

  11. Giudice L.C., Farrel E.M., Pham H., Lamson G., Rosenfeld R.G. Insulin-like growth factor binding proteins in the maternal serum throughout gestation and in the puerperium: effects of pregnancy-associated serum protease activity. J. Clin. Endocrinol. Metab. 1990, 71: 806–816.

    Article  CAS  PubMed  Google Scholar 

  12. Davenport M.L., Isley W.L., Pucilowska J.B., Pemberton L.B., Lyman S., Underwood L.E., Clemmons D.R. Insulin-like growth factor binding protein-3 proteolysis is induced after elective surgery. J. Clin. Endocrinol. Metab. 1992, 75: 590–595.

    CAS  PubMed  Google Scholar 

  13. Oh Y., Muller H.L., Lamson G., Rosenfeld R.G. Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. J. Biol. Chem. 1993, 268: 14964–14971.

    CAS  PubMed  Google Scholar 

  14. Pugliese G., Pricci F., Locuratolo N., Romano G., Giannini S., Cresci B., Rotella C.M., Di Mario U. Increased activity of the insulin-like growth factor system in mesangial cells cultured in high glucose conditions. Relation to glucose-enhanced extracellular matrix production. Diabetologia 1996, 39: 775–784.

    Article  CAS  PubMed  Google Scholar 

  15. Pugliese G., Pricci F., Romeo G., Pugliese F., Menè P., Giannini S., Galli G., Rotella C.M., Vlassara H., Di Mario U. Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated mechanism. Diabetes 1997, 46: 1881–1887.

    Article  CAS  PubMed  Google Scholar 

  16. Vanhee D., Gosset P., Wallaert B., Voisin C., Tonnel A.B. Mechanism of fibrosis in coal workers’ pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor-β and relationship to disease severity. Am. J. Respir. Crit. Care Med. 1994, 150: 1049–1055.

    Article  CAS  PubMed  Google Scholar 

  17. Allen J.T., Bloor C.A., Knight R.A., Spiteri M.A. Expression of insulin-like growth factor binding proteins in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. Am. J. Respir. Cell. Mol. Biol. 1998, 19: 250–258.

    Article  CAS  PubMed  Google Scholar 

  18. Harrison N.K., Cambrey A.D., Myers A.R., Southcott A.M., Black C.M., du Bois R.M., Lautent G.J., McAnult R.J. Insulin-like growth factor-I is partially responsible for fibroblast proliferation induced by bronchoalveolar lavage fluid from patients with systemic sclerosis. Clin. Sci. (Calch.) 1994, 86: 141–148.

    CAS  Google Scholar 

  19. Aston C., Jagirdar J., Lee T.C., Hur T., Hintz R.L., Rom W.N. Enhanced insulin-like growth factor molecules in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 1995, 151: 1597–1603.

    Article  CAS  PubMed  Google Scholar 

  20. Allen J.T., Knight R.A., Bloor C.A., Spiteri M.A. Enhanced insulin-like growth factor binding proteinrelated protein 2 (Connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am. J. Respir. Cell. Mol. Biol. 1999, 21: 693–700.

    Article  CAS  PubMed  Google Scholar 

  21. Scano G., Garcia Herreros P., Stendardi L., Degre S., De Coster A., Sergysels R. Cardiopulmonary adaptation to exercise in coal miners. Arch. Environ. Health 1990, 35: 360–366.

    Article  Google Scholar 

  22. European Community for Coal and Steel. Standardization of lung function tests. Eur. Respir. J. 1990, 6: 1–100.

    Google Scholar 

  23. Bradford M.M. A rapid and sensitive method for quantitation of micrograms quantities of protein, utilizing the principle of protein-dye binding. Anal. Biochem. 1976, 58: 541–548.

    Google Scholar 

  24. Hosselopp P., Seurin D., Segovia-Quinson B., Hardouin S., Binoux M. Analysis of serum insulin-like growth factor binding proteins and competitive binding studies. Anal. Biochem. 1986, 154: 138–143.

    Article  Google Scholar 

  25. Mohan S., Jennings J.C., Linkhard T.A., Baylink D.J. Primary structure of human skeletal growth factor: homology with human insulin-like growth factor II. Biochem. Biophys. Acta 1988, 966: 44–55.

    Article  CAS  PubMed  Google Scholar 

  26. Leary J.J., Brigati D.J., Ward D.C. Rapid and sensitive colorimetric method for visualizing biotin-labeled DNA probes hybridized to DNA or RNA immobilized on nitrocellulose: bio-blots. Proc. Natl. Acad. Sci. USA 1983, 80: 4045–4049.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Nakao Y., Hilliker S., Baylink D.J., Mohan S. Studies on the regulation of IGFBP-3 secretion in human osteosarcoma cells in vitro. J. Bone Miner. Res. 1994, 9: 865–872.

    Article  CAS  PubMed  Google Scholar 

  28. Baxter R.C., Martin J.L. Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma. J. Clin. Invest. 1986, 78: 1504–1512.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Clemmons D.R., Van Wyk J.J., Ridjway E.C., Kilman B., Kjellberg R.N., Underwood L.E. Evaluation of acromegaly by radioimmunoassay of somatomedin-C. N. Engl. J. Med. 1979, 301: 1138–1143.

    Article  CAS  PubMed  Google Scholar 

  30. Pugliese G., Pricci F., Locuratolo N., Romeo G., Romano G., Giannini S., Cresci B., Galli G., Rotella C.M., Di Mario U. Increased activity of Insulin-like growth factor system in mesangial cells cultured in high glucose condition. Relation to glucose-enhanced extracellular matrix production. Diabetologia 1996, 39: 775–784.

    Article  CAS  PubMed  Google Scholar 

  31. Fukuda Y., Ferrans V.J., Schoenberger C.I., Rennard S.I., Crystal R.G. Patterns of pulmonary structural remodeling after experimental paraquat toxicity: the morphogenesis of intralveolar fibrosis. Am. J. Pathol. 1986, 118: 452–475.

    Google Scholar 

  32. Katzenstein A.A., Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification. State of the art. Am. J. Respir. Crit. Care Med. 1998, 157: 1301–1315.

    Article  CAS  PubMed  Google Scholar 

  33. Homma S., Nagaoka I., Abe H., Takahashi K., Seyama K., Nukiwa T., Kira S. Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung. Am. J. Respir. Crit. Care Med. 1995, 152: 2084–2089.

    Article  CAS  PubMed  Google Scholar 

  34. Kelley J. Cytokines of the lung. Am. Rev. Respir. Dis. 1990, 141: 765–788.

    Article  CAS  PubMed  Google Scholar 

  35. Harrison N.K., Cambrey A.D., Myers A.R., Southcott A.M., Black C.M., du Bois R.M., Laurent G.J., McAnulty R.J. Insulin like growth factor I is partially responsible for fibroblast proliferation induced by bronchoalveolar lavage fluid from patients with systemic sclerosis. Clin. Sci. (Calch.) 1994, 86: 141–148.

    CAS  Google Scholar 

  36. Rom W.N., Paakko P. Activated alveolar macrophages express the insulinlike growth factor-I receptor. Am. J. Respir. Cell. Mol. Biol. 1991, 4: 432–439.

    Article  CAS  PubMed  Google Scholar 

  37. Blum W.F., Ranke M.B., Kietzmann K., Gauggel E., Zeisel H.J., Bierich J.R. A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J. Clin. Endocrinol. Metab. 1990, 70: 1292–1298.

    Article  CAS  PubMed  Google Scholar 

  38. Moser D.R., Lowe W.L. Jr., Dake B.L., Booth B.A., Boes M., Clemmons D.R., Bar R.S. Endothelial cells express insulin-like growth factorbinding proteins 2 to 6. Mol. Endocrinol. 1992, 6: 1805–1814.

    CAS  PubMed  Google Scholar 

  39. Maeda A., Hiyama K., Yamakido H., Ishioka S., Yamakido M. Increased expression of platelet-derived growth factor A and insulin-like growth factor I in BAL. Cells during the development of bleomycin-induced pulmonary fibrosis in mice. Chest 1996, 109: 780–786.

    Article  CAS  PubMed  Google Scholar 

  40. Rajaram S., Baylink D.J., Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr. Rev. 1997, 18: 801–831.

    CAS  PubMed  Google Scholar 

  41. Tucci M., Nyagard K., Tanswell B.V., Farber H.W., Hill D.J., Han V.K. Modulation of insulin-like growth factor (IGF) and IGF protein biosynthesis by hypoxia in cultured vascular endothelial cells. J. Endocrinol. 1998, 157: 13–24.

    Article  CAS  PubMed  Google Scholar 

  42. Blat C., Villaudy J., Binoux M. In vivo proteolysis of serum insulin-like growth factor (IGF) binding protein-3 results in increased availability of IGF to target cells. J. Clin. Invest. 1994, 93: 2286–2290

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Bach L.A., Rechler M.M. Insulin-like growth factor binding proteins. Diabetes Rev. 1995, 3: 38–61.

    Google Scholar 

  44. Keogh B.A., Crystal R.G. Pulmonary function testing in interstitial pulmonary disease. Chest 1980, 78: 856–865.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlo Maria Rotella.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pala, L., Giannini, S., Rosi, E. et al. Direct measurement of IGF-I and IGFBP-3 in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis. J Endocrinol Invest 24, 856–864 (2001). https://doi.org/10.1007/BF03343942

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03343942

Key-words

Navigation