Skip to main content
SpringerLink
Log in

Keratinocyte Growth Factor Decreases Pulmonary Edema, Transforming Growth Factor-Beta and Platelet-Derived Growth Factor-BB Expression, and Alveolar Type II Cell Loss in Bleomycin-Induced Lung Injury

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of bleomycin-induced lung injury. In this study, protective effects of KGF were explored during the earlier course of bleomycin-induced lung injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGFβ) and platelet-derived growth factor-BB (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGFβ protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II pneumocytes and Clara cells in KGF-pretreated lungs after a high dose of bleomycin were close to the normal in intact lungs. At the same dose of bleomycin injury, type II pneumocytes in saline-pretreated lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-injury level. In conclusion, KGF prevents bleomycin-induced end-stage pulmonary injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGFβ and PDGF-BB, and type II cell loss during the course of lung injury.

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

Access this article

Log in via an institution

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. Finch, P. W., S. S. Rubin, T. Miki, D. Ron, and S. A. Aaronson. 1989. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245:752–755.

    PubMed  Google Scholar 

  2. Panos, R. J., J. S. Rubin, S. A. Aaronson, and R. J. Mason. 1993. Keratinocyte growth factor and hepatocyte growth factor scatter factor after heparin-binding growth factor for alveolar type II cells in fibroblast-conditioned medium. J. Clin. Invest. 92:969–977.

    PubMed  Google Scholar 

  3. Ulich, T. R., E. S. Yi, K. Longmuir, S. Yin, R. Blitz, C. F. Morris, R. M. Housley, and G. F. Pierce. 1994. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J. Clin. Invest. 93:1298–1236.

    PubMed  Google Scholar 

  4. Yi, E. S., S. T. Williams, H. Lee, D. M. Malicki, E. M. Chin, S. Yin, J. Tarpley, and T. R. Ulich. 1996. Keratinocyte growth factor ameliorates radiation-and bleomycin-induced lung injury and mortality. Am. J. Pathol. 149:1963–1970.

    PubMed  Google Scholar 

  5. Panos, R. J., P. M. Bak, W. S. Simonet, J. S. Rubin, and L. J. Smith. 1995. Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats. J. Clin. Invest. 96:2026–2033.

    PubMed  Google Scholar 

  6. Yano, T., R. R. Deterding, W. S. Simonet, J. M. Shannon, and R. J. Mason. 1996. Keratinocyte growth factor reduces lung damage due to acid instillation in rats. Am. J. Respir. Cell. Mol. Biol. 15:433–442.

    PubMed  Google Scholar 

  7. Mason, C. M., B. P. H. Guery, W. R. Summer, and S. Nelson. 1996. Keratinocyte growth factor attenuates lung leak induced by alpha-naphthylthiourea in rats. Crit. Care Med. 24:925–931.

    Article  PubMed  Google Scholar 

  8. Rubin, J. S., H. Osada, P. W. Finch, W. G. Taylor, S. Rudikoff, and S. A. Aaronson. 1989. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 86:802–806.

    PubMed  Google Scholar 

  9. Ulich, T. R., L. R. Watson, S. Yin, K. Guo, P. Wang, H. Thang, and J. Del Castillo. 1991. The intracheal administration for endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-IL-1 TNF-induced inflammatory infiltrate. Am. J. Pathol. 138:1485–1496.

    PubMed  Google Scholar 

  10. Yi, E. S., D. G. Remick, Y. Lim, W. Tang, J. H. Williams, K. Guo, C. E. Nadziejko, A. A. Bedoya, S. Yin, and T. R. Ulich. 1996. Intratracheal injection of endotoxin: X, Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo. Inflammation 20:165–175.

    PubMed  Google Scholar 

  11. Danielpour, D., K. Y. Kim, L. L. Dart, S. Satanabe, A. B. Roberts, and M. B. Sporn. 1989. Sandwich enzyme-linked immunosabsorbent assays (SELISAs) quantitate and distinguish two forms of transforming growth factor-beta (TGFβ1 and TGFβ2) in complex biological fluids. Growth Factors 2:61–71.

    PubMed  Google Scholar 

  12. Masliah, E., M. Mallory, M. Alford, R. Deteresa, and T. Saitoh. 1995. PDGF is associated with neuronal and glial alterations of Alzheimer's disease. Neurobiology of Aging 16:549–556.

    Article  PubMed  Google Scholar 

  13. Harrison, J. H., D. G. Jr., Hoyt, and J. S. Lazo. 1989. Acute pulmonary toxicity of bleomycin: DNA scission and matrix protein mRNA levels in bleomycin-sensitive and-resistant strain of mice. Mol. Pharmacol. 36:231–238.

    PubMed  Google Scholar 

  14. Guery, B. P. H., C. M. Mason, E. P. Dobard, G. Beaucaire, W. R. Summer, and S. Nelson. 1997. Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. Am. J. Respir. Crit. Care Med. 155:1777–1784.

    PubMed  Google Scholar 

  15. Scneeberger, E. E., and K. M. McCarthy. 1986. Cytochemical localization for the Na, K-ATPase in rat type II pneumocytes. J. Appl. Physiol. 60:1584–1589.

    Article  PubMed  Google Scholar 

  16. Waters, C. M., U. Savla, and R. J. Panos. 1997. Keratinocyte growth factor protects airway epithelial cells from a hydrogen peroxide-induced permeability increase. Am. J. Crit. Care Med. 155:A173.

    Google Scholar 

  17. Lestrud, S. O., R. J. Panos, and P. H. S. Sporn. 1997. Keratinocyte growth factor upregulates leukotriene C4 synthesis in cultured rat alveolar type II cells. Am. J. Crit. Care Med. 155:A790.

    Google Scholar 

  18. Panos, R. J., and P. M. Pak. 1997. Keratinocyte growth factor increases whole lung SP-A, B, and C transcript levels. Am. J. Crit. Care Med. 155:A642.

    Google Scholar 

  19. Phan, S. H., and S. L. Kunkel. 1992. Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp. Lung Research 18:29–43.

    Google Scholar 

  20. Kelley, J. 1993. In Transforming growth factor beta. In Cytokines of the Lung, 1st ed., J. Kelley, editor. Marcel Dekker, New York, 101–137.

    Google Scholar 

  21. Raghow, R., P. Irish, and A. H. Kang. 1989. Coordinate regulation of TGF-beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J. Clin. Invest. 84:1836–1842.

    PubMed  Google Scholar 

  22. Breen, E., S. Shull, S. Burne, M. Absher, and J. Kelly. 1992. Bleomycin regulation of TGF-beta mRNA in rat lung fibroblasts. Am. J. Res. Cell Mol. Biol. 6:146–152.

    Google Scholar 

  23. Giri, S. N., D. M. Hyde, and M. A. Hollinger. 1993. Effect of antibody to TGF-beta on bleomycin induced accumulation of lung collagen in mice. Thorax 8:959–966.

    Google Scholar 

  24. Khalil, N., R. N. O'Connor, K. C. Flanders, S. Shing, and C. I. Whitman. 1994. Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats. Am. J. Physiol. 267:L498–507.

    PubMed  Google Scholar 

  25. Westergren-Thprsson, G., J. Hernnas, B. Sarnstrand, A. Oldberg, D. Heinegard, and A. Malmstrom. 1993. Altered expression of small proteoglycans, collagen, and TGF-beta 1 in developing bleomycin-induced fibrosis in rats. J. Clin. Invest. 92:632–637.

    PubMed  Google Scholar 

  26. Yi, E. S., A. Bedoya, H. Lee, E. Chin, W. Saunders, S. J. Kim, D. Danielpour, D. G. Remick, S. Yin, and T. R. Ulich. 1996. Radiation-induced lung injury in vivo: Expression of TGF-beta precedes fibrosis. Infl. 20:339–351.

    Google Scholar 

  27. Yoshida, M., J. Sakuma, S. Hayashi, K. Abe, I. Saito, S. Harada, M. Sakatani, S. Yamamoto, N. Matsumoto, U. Kaneda, and T. Kishimoto. 1995. A histologically distinctive interstitial pneumonia induced by overexpression of the IL-6, TGF-beta, and PDGF-B gene. Proc. Natl. Acad. Sci. U.S.A. 92:9570–9574.

    PubMed  Google Scholar 

  28. Kovacs, E. J., and J. Kelley. 1985. Secretion of macrophage-derived growth factor during acute lung injury by bleomycin. J. Leukocyte Biol. 37:1–14.

    PubMed  Google Scholar 

  29. Yi, E. S., H. Lee, S. Yin, P. Piguet, I. Sarosi, S. Kaufmann, J. Tarpley, N. S. Wang, and T. R. Ulich. 1996. PDGF causes pulmonary cell proliferation and collagen deposition in vivo. Am. J. Pathol. 149:539–548.

    PubMed  Google Scholar 

  30. Witschi, H. 1991. Role of the epithelium in lung repair: patterns of epithelial repair and pulmonary fibrosis. Chest 99:22S–25S.

    PubMed  Google Scholar 

  31. Bedrossian, C. W. M., M. A. Luna, B. Mackay, and B. Lightiger. 1973. Ultrastructure of pulmonary bleomycin toxicity. Cancer 32:44–51.

    PubMed  Google Scholar 

  32. Terzaghi, M., P. Nettesheim, and M. L. Williams. 1978. Repopulation of denuded tracheal grafts with normal, preneoplastic and neoplastic epithelial cell populations. Cancer Res. 38:4546–4553.

    PubMed  Google Scholar 

  33. Hagimoto, N., K. Kuwano, Y. Nomoto, R. Kunitake, and N. Hara. 1997. Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in mice. Am. J. Respir. Cell Mol. Biol. 16:91–101.

    PubMed  Google Scholar 

  34. Singh, G., S. L. Katyal, W. E. Brown, A. L. Kennedy, U. Singh, and M. L. Whong Chong. 1990. Clara cell 10 kDa protein (CC-10): comparison of structure and function with uteroglobin. Biochim. Biophys. Acta 1039:348–355.

    PubMed  Google Scholar 

  35. Hashimoto, S., K. Nakagawa, and K. Sueishi. 1996. Monkey Clara cell 10 kDa protein. Am. J. Respir. Cell. Mol. Biol. 15:361–366.

    PubMed  Google Scholar 

  36. Lesur, O., A. Bernard, K. Arsalane, R. Lauwerys, R. Begin, A. Antin, and D. Lane. 1995. Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro. Am. J. Respir. Crit. Care Med. 152:290–297.

    PubMed  Google Scholar 

  37. Johnston, C. J., G. W. Mango, J. N. Finkelstein, and B. R. Stripp. 1997. Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am. J. Respir. Cell. Mol. Biol. 17:147–155.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of California at San Diego School of Medicine, San Diego, California

    Eunhee S. Yi, Moses Salgado, Scott Williams, Eliezer Masliah & Thomas R. Ulich

  2. Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland

    Seong-Jin Kim

  3. Amgen, Inc., Thousand Oaks, California

    Songmei Yin & Thomas R. Ulich

Authors
  1. Eunhee S. Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moses Salgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seong-Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Songmei Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas R. Ulich
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yi, E.S., Salgado, M., Williams, S. et al. Keratinocyte Growth Factor Decreases Pulmonary Edema, Transforming Growth Factor-Beta and Platelet-Derived Growth Factor-BB Expression, and Alveolar Type II Cell Loss in Bleomycin-Induced Lung Injury. Inflammation 22, 315–325 (1998). https://doi.org/10.1023/A:1022304317111

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022304317111

Keywords

Search

Navigation