Skip to main content
SpringerLink
Log in

Pulmonary Alveolar Proteinosis

What is the Role of GM-CSF in Disease Pathogenesis and Treatment?

  • Commentary
  • Published:
Treatments in Respiratory Medicine

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

Table I
Table II

References

  1. Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med 1958; 258: 1123–43

    Article  PubMed  CAS  Google Scholar 

  2. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002; 166: 215–35

    Article  PubMed  Google Scholar 

  3. Levinson B, Jones RS, Wintrobe MM. Un cas de thrombocythémie avec polyglobulie chez une jeune femme avec envahissement pulmonaire par une substance éosinophile hyaline. Sang 1957; 28: 224–5

    PubMed  CAS  Google Scholar 

  4. Linell F, Magnusson B, Nordén Å. Cryptococcosis: review and report of a case. Acta Derm Venereol 1953; 33: 103–22

    PubMed  CAS  Google Scholar 

  5. Bergman F, Linell F. Cryptococcosis as a cause of pulmonary alveolar proteinosis. Acta Pathol Microbiol Scand 1961; 53: 217–24

    Article  PubMed  CAS  Google Scholar 

  6. Levinson B, Jones RS, Wintrobe MM, et al. Thrombocythemia and pulmonary intra-alveolar coagulum in a young woman. Blood 1958; 13: 959–71

    PubMed  CAS  Google Scholar 

  7. Plenk HP, Swift SA, Chambers WL, et al. Pulmonary alveolar proteinosis: a new disease? Radiology 1960; 74: 928–38

    PubMed  CAS  Google Scholar 

  8. Doyle AP, Balcerzak SP, Wells CL, et al. Pulmonary alveolar proteinosis with hematologic disorders. Arch Intern Med 1963; 112: 940–6

    Article  PubMed  CAS  Google Scholar 

  9. Burgess AW, Camakaris J, Metcalf D. Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem 1977; 252: 1998–2003

    PubMed  CAS  Google Scholar 

  10. Gough NM, Gough J, Metcalf D, et al. Molecular cloning of cDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor. Nature 1984; 309: 763–7

    Article  PubMed  CAS  Google Scholar 

  11. Bradley TR, Metcalf D. The growth of mouse bone marrow cells in vitro. Aust J Exp Biol Med Sci 1966; 44: 287–99

    Article  PubMed  CAS  Google Scholar 

  12. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med 1992; 327: 28–35

    Article  PubMed  CAS  Google Scholar 

  13. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (2). N Engl J Med 1992; 327: 99–106

    Article  PubMed  CAS  Google Scholar 

  14. Armitage JO. Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1998; 92: 4491–508

    PubMed  CAS  Google Scholar 

  15. Gearing DP, King JA, Gough NM, et al. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J 1989; 8: 3667–76

    PubMed  CAS  Google Scholar 

  16. Evans CA, Ariffin S, Pierce A, et al. Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors. Blood 2002; 100: 3164–74

    Article  PubMed  CAS  Google Scholar 

  17. Carr PD, Gustin SE, Church AP, et al. Structure of the complete extracellular domain of the common b subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration. Cell 2001; 104: 291–300

    Article  PubMed  CAS  Google Scholar 

  18. Miyajima A, Mui AL, Ogorochi T, et al. Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. Blood 1993; 82: 1960–74

    PubMed  CAS  Google Scholar 

  19. Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colonystimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994; 91: 5592–6

    Article  PubMed  CAS  Google Scholar 

  20. Dranoff G, Crawford AD, Sadelain M, et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994; 264: 713–6

    Article  PubMed  CAS  Google Scholar 

  21. Robb L, Drinkwater C, Metcalf D, et al. Hematopoietic and lung abnormalities in mice with a null mutation of the common b subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc Natl Acad Sci USA 1995; 92: 9565–9

    Article  PubMed  CAS  Google Scholar 

  22. Nishinakamura R, Nakayama N, Hirabayashi Y, et al. Mice deficient for the IL-3/GM-CSF/IL-5 be receptor exhibit lung pathology and impaired immune response, while bIL3 receptor-deficient mice are normal. Immunity 1995; 2: 211–22

    Article  PubMed  CAS  Google Scholar 

  23. Trapnell BC, Whitsett JA. GM-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol 2002; 64: 775–802

    Article  PubMed  CAS  Google Scholar 

  24. Venkateshiah SB, Thomassen MJ, Kavuru MS. Pulmonary alveolar proteinosis: clinical manifestations and optimal treatment strategies. Treat Respir Med 2004; 3(4): 217–27

    Article  PubMed  CAS  Google Scholar 

  25. Stratton JA, Sieger L, Wasserman K. The immunoinhibitory activities of the lung lavage materials and sera from patients with pulmonary alveolar proteinosis. J Clin Lab Immunol 1981; 5: 81–6

    PubMed  CAS  Google Scholar 

  26. Müller-Quernheim J, Schopf RE, Benes P, et al. A macrophage-suppressing 40-kD protein in a case of pulmonary alveolar proteinosis. Klin Wochenschr 1987; 65: 893–7

    Article  PubMed  Google Scholar 

  27. Carre PC, Didier AP, Pipy BR, et al. The lavage fluid from a patient with alveolar proteinosis inhibits the in vitro chemiluminescence response and arachidonic acid metabolism of normal guinea pig alveolar macrophages. Am Rev Respir Dis 1990; 142: 1068–72

    PubMed  CAS  Google Scholar 

  28. Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte-macrophage colony stimulating factor. J Exp Med 1999; 190: 875–80

    Article  PubMed  CAS  Google Scholar 

  29. Kitamura T, Uchida K, Tanaka N, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 162: 658–62

    PubMed  CAS  Google Scholar 

  30. Tanaka N, Watanabe J, Kitamura T, et al. Lungs of patients with idiopathic pulmonary alveolar proteinosis express a factor which neutralizes granulocyte-macrophage colony stimulating factor. FEBS Lett 1999; 442: 246–50

    Article  PubMed  CAS  Google Scholar 

  31. Bonfield TL, Kavuru MS, Thomassen MJ. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol 2002; 105: 342–50

    Article  PubMed  CAS  Google Scholar 

  32. Bonfield TL, Russell D, Burgess S, et al. Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol 2002; 27: 481–6

    PubMed  CAS  Google Scholar 

  33. Latzin P, Tredano M, Nicolai T, et al. GM-CSF auto antibodies in serum and broncho-alveolar lavage (BAL) of children and adults with pulmonary alveolar proteinosis (PAP) [abstract]. Am J Respir Crit Care Med 2003; 167(7 Suppl.): A951

    Google Scholar 

  34. Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis. N Engl J Med 1996; 335: 1924–5

    Article  PubMed  CAS  Google Scholar 

  35. Seymour JF, Presneill JJ, Schoch OD, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med 2001; 163: 524–31

    PubMed  CAS  Google Scholar 

  36. Seymour JF, Begley CG, Dirksen U, et al. Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood 1998; 92: 2657–67

    PubMed  CAS  Google Scholar 

  37. Shibata Y, Berclaz PY, Chroneos ZC, et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 2001; 15: 557–67

    Article  PubMed  CAS  Google Scholar 

  38. Sieger L, Stratton JA, Wasserman K. Pulmonary washings and blood in pulmonary alveolar proteinosis [letter]. Pediatr Res 1977; 11: 579

    Article  Google Scholar 

  39. Golde DW, Territo M, Finley TN, et al. Defective lung macrophages in pulmonary alveolar proteinosis. Ann Intern Med 1976; 85: 304–9

    PubMed  CAS  Google Scholar 

  40. Iyonaga K, Suga M, Yamamoto T, et al. Elevated bronchoalveolar concentrations of MCP-1 in patients with pulmonary alveolar proteinosis. Eur Respir J 1999; 14: 383–9

    Article  PubMed  CAS  Google Scholar 

  41. Nakata K, Trapnell BC, Hamano E, et al. Reduced expression of PU.1 and C/EBP by alveolar macrophages in idiopathic pulmonary alveolar proteinosis [abstract]. Am J Respir Crit Care Med 2003; 167 Suppl.: A952

    Google Scholar 

  42. Bonfield TL, Malur B, Raychaudhuri B, et al. Alveolar macrophage differentiation is decreased in pulmonary alveolar proteinosis (PAP) [abstract]. Am J Respir Crit Care Med 2003; 167 Suppl.: A702

    Article  Google Scholar 

  43. Paine III R, Morris SB, Jin H, et al. Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice. Am J Physiol Lung Cell Mol Physiol 2001; 281: L1210–8

    PubMed  CAS  Google Scholar 

  44. Berclaz PY, Shibata Y, Whitsett JA, et al. GM-CSF, via PU.1, regulates alveolar macrophage FcgR-mediated phagocytosis and the IL-18/IFN-g-mediated molecular connection between innate and adaptive immunity in the lung. Blood 2002; 100: 4193–200

    Article  PubMed  CAS  Google Scholar 

  45. Berclaz PY, Zsengellér Z, Shibata Y, et al. Endocytic internalization of adenovirus, nonspecific phagocytosis, and cytoskeletal organization are coordinately regulated in alveolar macrophages by GM-CSF and PU.1. J Immunol 2002; 169: 6332–42

    PubMed  CAS  Google Scholar 

  46. Bury T, Corhay JL, Saint-Remy P, et al. Protéinose alvéolaire: restauration fonctionnelle des macrophages alvéolaires aprés lavage thérapeutique. Rev Mal Respir 1989; 6: 373–5

    PubMed  CAS  Google Scholar 

  47. Nugent KM, Pesanti EL. Macrophage function in pulmonary alveolar proteinosis. Am Rev Respir Dis 1983; 127: 780–1

    PubMed  CAS  Google Scholar 

  48. Harris JO. Pulmonary alveolar proteinosis: abnormal in vitro function of alveolar macrophages. Chest 1979; 76: 156–9

    Article  PubMed  CAS  Google Scholar 

  49. Reed JA, Ikegami M, Cianciolo ER, et al. Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice. Am J Physiol 1999; 276: L556–63

    PubMed  CAS  Google Scholar 

  50. Zsengellér ZK, Reed JA, Bachurski CJ, et al. Adenovirus-mediated granulocyte-macrophage colony-stimulating factor improves lung pathology of pulmonary alveolar proteinosis in granulocyte-macrophage colony-stimulating factor-deficient mice. Hum Gene Ther 1998; 9: 2101–9

    Article  PubMed  Google Scholar 

  51. Scott CL, Hughes DA, Cary D, et al. Functional analysis of mature hematopoietic cells from mice lacking the bc chain of the granulocyte-macrophage colonystimulating factor receptor. Blood 1998; 92: 4119–27

    PubMed  CAS  Google Scholar 

  52. Scott CL, Begley CG. The beta common chain (bc) of the granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5 receptors. Int J Biochem Cell Biol 1999; 31: 1011–5

    Article  PubMed  CAS  Google Scholar 

  53. Basu S, Dunn AR, Marino MW, et al. Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol 1997; 159: 1412–7

    PubMed  CAS  Google Scholar 

  54. Enzler T, Gillessen S, Manis JP, et al. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med 2003; 197: 1213–9

    Article  PubMed  CAS  Google Scholar 

  55. Yoshida M, Ikegami M, Reed JA, et al. GM-CSF regulates protein and lipid catabolism by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2001; 280: L379–86

    PubMed  CAS  Google Scholar 

  56. Zhan Y, Basu S, Lieschke GJ, et al. Functional deficiencies of peritoneal cells from gene-targeted mice lacking G-CSF or GM-CSF. J Leukoc Biol 1999; 65: 256–64

    PubMed  CAS  Google Scholar 

  57. Scott CL, Roe L, Curtis J, et al. Mice unresponsive to GM-CSF are unexpectedly resistant to cutaneous Leishmania major infection. Microbes Infect 2000; 2: 1131–8

    Article  PubMed  CAS  Google Scholar 

  58. Seymour JF, Lieschke GJ, Grail D, et al. Mice lacking both granulocyte colonystimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 1997; 90: 3037–49

    PubMed  CAS  Google Scholar 

  59. Zhan Y, Lieschke GJ, Grail D, et al. Essential roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF in the sustained hematopoietic response of listeria monocytogenes-infected mice. Blood 1998; 91: 863–9

    PubMed  CAS  Google Scholar 

  60. Robertson SA, Roberts CT, Farr KL, et al. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod 1999; 60: 251–61

    Article  PubMed  CAS  Google Scholar 

  61. Gilchrist RB, Rowe DB, Ritter LJ, et al. Effect of granulocyte-macrophage colony-stimulating factor deficiency on ovarian follicular cell function. J Reprod Fertil 2000; 120: 283–92

    Article  PubMed  CAS  Google Scholar 

  62. Jasper MJ, Robertson SA, Van der Hoek KH, et al. Characterization of ovarian function in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod 2000; 62: 704–13

    Article  PubMed  CAS  Google Scholar 

  63. Noguchi Y, Wada H, Marino MW, et al. Regulation of IFN-g production in granulocyte-macrophage colony-stimulating factor-deficient mice. Eur J Immunol 1998; 28: 3980–8

    Article  PubMed  CAS  Google Scholar 

  64. Wada H, Noguchi Y, Marino MW, et al. T cell functions in granulocyte/macrophage colony-stimulating factor deficient mice. Proc Natl Acad Sci U S A 1997; 94: 12557–61

    Article  PubMed  CAS  Google Scholar 

  65. Gillessen S, Mach N, Small C, et al. Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity. Blood 2001; 97: 922–8

    Article  PubMed  CAS  Google Scholar 

  66. Burnham K, Robb L, Scott CL, et al. Effect of granulocyte-macrophage colonystimulating factor on the generation of epidermal Langerhans cells. J Interferon Cytokine Res 2000; 20: 1071–6

    Article  PubMed  CAS  Google Scholar 

  67. Campbell IK, Rich MJ, Bischof RJ, et al. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol 1998; 161: 3639–44

    PubMed  CAS  Google Scholar 

  68. McQualter JL, Darwiche R, Ewing C, et al. Granulocyte macrophage colonystimulating factor: a new putative therapeutic target in multiple sclerosis. J Exp Med 2001; 194: 873–82

    Article  PubMed  CAS  Google Scholar 

  69. Kitching AR, Huang RX, Turner AL, et al. The requirement for granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in leukocyte-mediated immune glomerular injury. J Am Soc Nephrol 2002; 13: 350–8

    PubMed  CAS  Google Scholar 

  70. Venkateshiah SB, Avecillas JF, Gupta M, et al. Antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in pulmonary alveolar proteinosis (PAP) is a specific phenomenon and not part of a generalized autoimmune process [abstract]. Am J Respir Crit Care Med 2003; 167 Suppl.: A951

    Google Scholar 

  71. Scott EW, Simon MC, Anastasi J, et al. Requirement of transcription factor PU. 1 in the development of multiple hematopoietic lineages. Science 1994; 265:1573–7

    Article  PubMed  CAS  Google Scholar 

  72. Anderson KL, Smith KA, Perkin H, et al. PU.1 and the granulocyte- and macrophage colony-stimulating factor receptors play distinct roles in late-stage myeloid cell differentiation. Blood 1999; 94: 2310–8

    PubMed  CAS  Google Scholar 

  73. Paine III R, Preston AM, Wilcoxen S, et al. Granulocyte-macrophage colonystimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice. J Immunol 2000; 164: 2602–9

    PubMed  CAS  Google Scholar 

  74. Moore BB, Coffey MJ, Christensen P, et al. GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism. J Immunol 2000; 165: 4032–9

    PubMed  CAS  Google Scholar 

  75. Kavuru MS, Sullivan EJ, Piccin R, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161: 1143–8

    PubMed  CAS  Google Scholar 

  76. Seymour JF, Doyle IR, Nakata K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003; 58: 252–7

    Article  PubMed  CAS  Google Scholar 

  77. Uchida K, Nakata K, Trapnell BC, et al. High affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood 2004; 103: 1089–98.

    Article  PubMed  CAS  Google Scholar 

  78. Hamano E, Nakata K, Uchida K, et al. Neutralizing activity of sera from patients with idiopathic pulmonary alveolar proteinosis against the biological actions of GM-CSF are correlated with disease severity [abstract]. Am J Respir Crit Care Med 2003; 167(7 Suppl.): A952

    Google Scholar 

  79. Anderson PM, Markovic SN, Sloan JA, et al. Aerosol granulocyte-macrophage colony-stimulating factor: a low toxicity, lung-specific biologic therapy in patients with lung metastases. Clin Cancer Res 1999; 5: 2316–23

    PubMed  CAS  Google Scholar 

  80. Rao RD, Anderson PM, Arndt CA, et al. Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol 2003; 26: 493–8

    Article  PubMed  CAS  Google Scholar 

  81. Wylam ME, Ten RM, Katzman JA, et al. Aerosolized GM-CSF improves pulmonary function in idiopathic pulmonary alveolar proteinosis [abstract]. Am J Respir Crit Care Med 2000; 161 Suppl. A889

    Google Scholar 

  82. Tazawa R, Ishimoto O, Ohta H, et al. Aerosolized granulocyte-macrophage colony-stimulating factor (GM-CSF) and treatment for pulmonary alveolar proteinosis (PAP) [abstract]. Am J Respir Crit Care Med 2003; 167(7 Suppl.): A953

    Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this commentary. The authors have no conflicts of interest that are directly relevant to the content of this commentary.

Author information

Authors and Affiliations

  1. Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    John F. Seymour

  2. Intensive Care Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Jeffrey J. Presneill

Authors
  1. John F. Seymour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey J. Presneill
    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

Seymour, J.F., Presneill, J.J. Pulmonary Alveolar Proteinosis. Treat Respir Med 3, 229–234 (2004). https://doi.org/10.2165/00151829-200403040-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00151829-200403040-00003

Keywords

Search

Navigation